TBC1D8B

Chr XX-linked

TBC1 domain family member 8B

Also known as: GRAMD8B, NPHS20

NCBI Gene: 54885ENSG00000133138UniProt: Q0IIM8

The protein functions as a RAB11B GTPase-activating protein involved in vesicular recycling. Mutations cause X-linked nephrotic syndrome, type 20, affecting kidney function. This gene shows extremely low tolerance to loss-of-function variants (pLI ~1.0), indicating it is highly constrained and essential for normal cellular function.

Summary from RefSeq, OMIM, UniProt
Research Assistant →

Primary Disease Associations & Inheritance

Nephrotic syndrome, type 20MIM #301028
X-linked
0
Active trials
1
Pubs (1 yr)
44
P/LP submissions
5%
P/LP missense
0.74
LOEUF
Multiple*
Mechanism· predicted
Clinical Summary— TBC1D8B
🧬
Gene-Disease Validity (ClinGen)
nephrotic syndrome, type 20 · XLModerate

Moderate evidence — consider for supplementary testing

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
42 unique Pathogenic / Likely Pathogenic· 180 VUS of 500 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
0.74LOEUF
pLI 0.000
Z-score 2.83
OE 0.51 (0.36–0.74)
Tolerant

Typical tolerance to LoF variation

Missense Constraint
0.06Z-score
OE missense 0.99 (0.91–1.08)
372 obs / 375.1 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.51 (0.36–0.74)
0≤0.351.4
Missense OE0.99 (0.91–1.08)
0≤0.61.4
Synonymous OE0.91
0≤1.21.6
LoF obs/exp: 20 / 39.1Missense obs/exp: 372 / 375.1Syn Z: 0.84
DN
0.6938th %ile
GOF
0.7029th %ile
LOF
0.2777th %ile

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

GOFprediction above median
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

500 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic36
Likely Pathogenic6
VUS180
Likely Benign51
Benign27
Conflicting10
36
Pathogenic
6
Likely Pathogenic
180
VUS
51
Likely Benign
27
Benign
10
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
2
34
0
36
Likely Pathogenic
2
0
4
0
6
VUS
2
163
14
1
180
Likely Benign
2
11
20
18
51
Benign
0
3
17
7
27
Conflicting
—10
Total61798926310

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

View in ClinVar →

Protein Context — Lollipop Plot

TBC1D8B · 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 4 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