TBC1D7

Chr 6AR

TBC1 domain family member 7

Also known as: MGCPH, PIG51, TBC7

NCBI Gene: 51256ENSG00000145979UniProt: Q9P0N9

This gene encodes a member of the TBC-domain containing protein family. The encoded protein functions as a subunit of the tuberous sclerosis TSC1-TSC2 complex which plays a role in the regulation of cellular growth and differentiation. Mutations in this gene have been associated with autosomal recessive megalencephaly. Alternative splicing results in multiple transcript variants. Naturally occurring readthrough transcription occurs between this locus and downstream LOC100130357. [provided by RefSeq, Jan 2016]

Primary Disease Associations & Inheritance

Macrocephaly/megalencephaly syndrome, autosomal recessiveMIM #248000
AR
181
ClinVar variants
33
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— TBC1D7
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
33 Pathogenic / Likely Pathogenic· 70 VUS of 181 total submissions

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.
1.61LOEUF
pLI 0.000
Z-score -0.29
OE 1.08 (0.74–1.61)
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.
0.14Z-score
OE missense 0.97 (0.85–1.10)
168 obs / 173.4 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.1.08 (0.74–1.61)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.97 (0.85–1.10)
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.1.06
0≤1.21.6
LoF obs/exp: 17 / 15.8Missense obs/exp: 168 / 173.4Syn Z: -0.38

ClinVar Variant Classifications

181 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic30
Likely Pathogenic3
VUS70
Likely Benign43
Benign30
Conflicting5
30
Pathogenic
3
Likely Pathogenic
70
VUS
43
Likely Benign
30
Benign
5
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
4
0
26
0
30
Likely Pathogenic
2
0
1
0
3
VUS
0
62
8
0
70
Likely Benign
0
6
15
22
43
Benign
0
2
22
6
30
Conflicting
—5
Total6707228181

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

View in ClinVar →

Protein Context — Lollipop Plot

TBC1D7 · 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

Macrocephaly/megalencephaly syndrome, autosomal recessive

MIM #248000

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Two genome-wide interaction loci modify the association of nonsteroidal anti-inflammatory drugs with colorectal cancer.
Drew DA et al.·Sci Adv
2024
Clinical-Genetic Approach to Conditions with Macrocephaly and ASD/Behaviour Abnormalities: Variants in PTEN and PPP2R5D Are the Most Recurrent Gene Mutations in a Patient-Oriented Diagnostic Strategy.
L'Erario FF et al.·Genes (Basel)
2025
TBC1 domain-containing proteins are frequently involved in triple-negative breast cancers in connection with the induction of a glycolytic phenotype.
Lupi M et al.·Cell Death Dis
2024
Disruption of TBC1D7, a subunit of the TSC1-TSC2 protein complex, in intellectual disability and megalencephaly.
Capo-Chichi JM et al.·J Med Genet
2013
Integrated proteomics and transcriptomics analysis reveals key regulatory genes between ER-positive/PR-positive and ER-positive/PR-negative breast cancer.
Lu Z et al.·BMC Cancer
2025
Genomic Alterations in PIK3CA-Mutated Breast Cancer Result in mTORC1 Activation and Limit the Sensitivity to PI3Kα Inhibitors.
Cai Y et al.·Cancer Res
2021
Focal malformations of cortical development: new vistas for molecular pathogenesis.
Lim KC et al.·Neuroscience
2013Review
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