DENND6B

Chr 22

DENN domain containing 6B

Also known as: AFI1B, FAM116B

NCBI Gene: 414918 ENSG00000205593 UniProt: Q8NEG7 OMIM: 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.

OMIM ResearchSummary from RefSeq, UniProt

Enables guanyl-nucleotide exchange factor activity. Predicted to be located in cytosol. Predicted to be active in recycling endosome. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.83

Clinical Summary— DENND6B

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

102 VUS of 128 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 OE?0.57 (0.39–0.83)

0≤0.351.4

Missense OE?0.87 (0.78–0.95)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 19 / 33.5Missense obs/exp: 280 / 323.7Syn Z: -0.02

This gene — mechanism propensity

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

128 submitted variants in ClinVar

ClinVar

Classification Summary

VUS102

Likely Benign2

102

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	102	0	102
Likely Benign	1	1	2
Benign	0	0	0
Total	103	1	104

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

View in ClinVar →

142 pathogenic / likely-pathogenic (of 153) ClinVar copy-number / structural variants overlap DENND6B — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →