TUBGCP4

Chr 15AR

tubulin gamma complex component 4

Also known as: 76P, GCP-4, GCP4, Grip76, MCCRP3

NCBI Gene: 27229 ENSG00000137822 UniProt: Q9UGJ1 OMIM: 609610

This gene encodes a component of the gamma-tubulin ring complex that mediates microtubule nucleation at centrosomes, which is critical for centrosome duplication and spindle formation. Mutations cause microcephaly and chorioretinopathy, autosomal recessive, 3, affecting brain development and the retina. The gene shows high constraint against loss-of-function variants (LOEUF 0.716) and follows autosomal recessive inheritance.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a component of the gamma-tubulin ring complex, which is required for microtubule nucleation. In mammalian cells, the protein localizes to centrosomes in association with gamma-tubulin. Crystal structure analysis revealed a structure composed of five helical bundles arranged around conserved hydrophobic cores. An exposed surface area located in the C-terminal domain is essential and sufficient for direct binding to gamma-tubulin. Mutations in this gene that alter microtubule organization are associated with microcephaly and chorioretinopathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2015]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Microcephaly and chorioretinopathy, autosomal recessive, 3MIM #616335

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Microcephaly and chorioretinopathy, autosomal recessive; no ClinGen or GenCC tier

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.72

LOEUF

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.72LOEUF

pLI 0.000

Z-score 3.03

OE 0.50 (0.35–0.72)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

2.58Z-score

OE missense 0.62 (0.56–0.69)

227 obs / 365.8 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.50 (0.35–0.72)

0≤0.351.4

Missense OE?0.62 (0.56–0.69)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 21 / 42.2Missense obs/exp: 227 / 365.8Syn Z: 0.42

Background carrier burden — how many people carry a rare variant somewhere in TUBGCP4?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 83

646 rare PASS variants

Rare truncating (LoF)

1 in 1,400

126 rare PASS variants

Rare synonymous (reference)

1 in 130

311 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TUBGCP4. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 150	1 in 1,700
South Asian	~43k	1 in 110	1 in 1,700
Remaining (unassigned)	~30k	1 in 93	1 in 1,100
European (Finnish)	~27k	1 in 230	1 in 1,800
Admixed American	~22k	1 in 130	1 in 1,300
African / African American	~21k	1 in 130	1 in 1,300
East Asian	~20k	1 in 140	1 in 4,000
Ashkenazi Jewish	~13k	1 in 250	1 in 1,900
Middle Eastern	~2,884	1 in 110	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 17 of 18 coding exons well covered in gnomAD exomes; exon 9 marginal. Genomes: 17 of 18 (exon 9 below).? see exons ↓