DENND6B

Chr 22

DENN domain containing 6B

Also known as: AFI1B, FAM116B

NCBI Gene: 414918ENSG00000205593UniProt: Q8NEG7OMIM: 620562

The protein functions as a guanine nucleotide exchange factor for RAB14 and has lesser activity toward RAB35, regulating vesicle trafficking in recycling endosomes. Mutations cause autosomal recessive neurodevelopmental disorders with intellectual disability, seizures, and movement abnormalities. This gene is highly constrained against loss-of-function variants in the population.

OMIMResearchSummary from RefSeq, UniProt
MultiplemechanismLOEUF 0.83
Clinical Summary— DENND6B
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
141 unique Pathogenic / Likely Pathogenic· 110 VUS of 279 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
0.83LOEUF
pLI 0.000
Z-score 2.32
OE 0.57 (0.39–0.83)
Tolerant

Typical tolerance to LoF variation

Missense Constraint
0.86Z-score
OE missense 0.87 (0.78–0.95)
280 obs / 323.7 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.57 (0.39–0.83)
0≤0.351.4
Missense OE0.87 (0.78–0.95)
0≤0.61.4
Synonymous OE1.00
0≤1.21.6
LoF obs/exp: 19 / 33.5Missense obs/exp: 280 / 323.7Syn Z: -0.02
DN
0.6843th %ile
GOF
0.6639th %ile
LOF
0.3261th %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

279 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic138
Likely Pathogenic3
VUS110
Likely Benign2
Benign2
138
Pathogenic
3
Likely Pathogenic
110
VUS
2
Likely Benign
2
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
138
0
138
Likely Pathogenic
0
0
3
0
3
VUS
0
101
9
0
110
Likely Benign
0
1
0
1
2
Benign
0
0
2
0
2
Total01021521255

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

View in ClinVar →

Protein Context — Lollipop Plot

DENND6B · 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 1 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC

No open access results found

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