TBC1D2

Chr 9

TBC1 domain family member 2

Also known as: PARIS-1, PARIS1, TBC1D2A

NCBI Gene: 55357ENSG00000095383UniProt: Q9BYX2OMIM: 609871

This protein functions as a GTPase-activating protein for RAB7A and acts as a signal effector linking RAC1 and RAB7A to regulate cadherin degradation and cell-cell adhesion. Mutations in TBC1D2 cause intellectual disability with macrocephaly, seizures, and behavioral abnormalities, typically with childhood onset. The condition follows an autosomal dominant inheritance pattern.

OMIMResearchSummary from RefSeq, UniProt
MultiplemechanismLOEUF 0.79
Clinical Summary— TBC1D2
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
31 unique Pathogenic / Likely Pathogenic· 134 VUS of 205 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
0.79LOEUF
pLI 0.000
Z-score 2.63
OE 0.55 (0.39–0.79)
Tolerant

Typical tolerance to LoF variation

Missense Constraint
1.05Z-score
OE missense 0.87 (0.81–0.94)
484 obs / 553.8 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.55 (0.39–0.79)
0≤0.351.4
Missense OE0.87 (0.81–0.94)
0≤0.61.4
Synonymous OE0.85
0≤1.21.6
LoF obs/exp: 22 / 39.9Missense obs/exp: 484 / 553.8Syn Z: 1.84
DN
0.76top 25%
GOF
0.73top 25%
LOF
0.2386th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median
GOFprediction 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

205 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic27
Likely Pathogenic4
VUS134
Likely Benign14
Benign8
27
Pathogenic
4
Likely Pathogenic
134
VUS
14
Likely Benign
8
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
27
0
27
Likely Pathogenic
0
0
4
0
4
VUS
0
126
8
0
134
Likely Benign
0
14
0
0
14
Benign
0
4
0
4
8
Total0144394187

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

View in ClinVar →

Protein Context — Lollipop Plot

TBC1D2 · 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