The DENND3 protein functions as a guanine nucleotide exchange factor that activates RAB12, regulating autophagy in response to starvation and controlling protein transport from recycling endosomes to lysosomes. Mutations cause neurodevelopmental disorders with intellectual disability, though the inheritance pattern has not been clearly established. The gene shows minimal constraint against loss-of-function variants (very low pLI score), suggesting tolerance to complete protein loss.

OMIMResearchSummary from RefSeq, UniProt
LOEUF 0.66
Clinical SummaryDENND3
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Tolerant — LoF & missense variants common in population
LoF Constraint
0.66LOEUF
pLI 0.000
Z-score 3.65
OE 0.48 (0.360.66)
Tolerant

Typical tolerance to LoF variation

Missense Constraint
2.37Z-score
OE missense 0.75 (0.700.81)
556 obs / 736.7 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios
LoF OE0.48 (0.360.66)
00.351.4
Missense OE0.75 (0.700.81)
00.61.4
Synonymous OE0.99
01.21.6
LoF obs/exp: 28 / 58.0Missense obs/exp: 556 / 736.7Syn Z: 0.18

ClinVar Variant Classifications

0 submitted variants in ClinVar

Protein Context — Lollipop Plot

DENND3 · 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

No active trials found for this gene.

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Clinical Literature
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