TBC1D4

Chr 13

TBC1 domain family member 4

Also known as: AS160, NIDDM5

NCBI Gene: 9882ENSG00000136111UniProt: O60343OMIM: 612465

The protein functions as a Rab-GTPase-activating protein that regulates insulin-dependent trafficking of the glucose transporter GLUT4, controlling glucose uptake into skeletal muscle and fat tissues. Homozygous mutations cause increased risk for type 2 diabetes with elevated circulating glucose and insulin levels following glucose ingestion, following autosomal recessive inheritance. The gene shows very low constraint against loss-of-function variants, consistent with a recessive disorder pattern.

OMIMResearchSummary from RefSeq, UniProt
DNmechanismLOEUF 0.921 OMIM phenotype
Clinical Summary— TBC1D4
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
69 unique Pathogenic / Likely Pathogenic· 177 VUS of 337 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint
0.92LOEUF
pLI 0.000
Z-score 2.11
OE 0.72 (0.56–0.92)
Tolerant

Typical tolerance to LoF variation

Missense Constraint
0.70Z-score
OE missense 0.93 (0.87–0.99)
649 obs / 701.1 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.72 (0.56–0.92)
0≤0.351.4
Missense OE0.93 (0.87–0.99)
0≤0.61.4
Synonymous OE1.03
0≤1.21.6
LoF obs/exp: 46 / 64.3Missense obs/exp: 649 / 701.1Syn Z: -0.36
DN
0.6646th %ile
GOF
0.5758th %ile
LOF
0.3841th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

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.

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

ClinVar Variant Classifications

337 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic69
VUS177
Likely Benign13
Benign52
Conflicting2
69
Pathogenic
177
VUS
13
Likely Benign
52
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
69
0
69
Likely Pathogenic
0
0
0
0
0
VUS
1
165
9
2
177
Likely Benign
1
7
2
3
13
Benign
0
9
36
7
52
Conflicting
—2
Total218111612313

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

View in ClinVar →

Protein Context — Lollipop Plot

TBC1D4 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients