DENND3

Chr 8

DENN domain containing 3

NCBI Gene: 22898 ENSG00000105339 OMIM: 617503

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.

OMIM ResearchSummary from RefSeq, UniProt

Enables guanyl-nucleotide exchange factor activity. Predicted to be involved in endosome to lysosome transport; protein catabolic process; and regulation of Rab protein signal transduction. Predicted to be located in cytosol. Predicted to be active in cytoplasmic vesicle. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

LOEUF 0.66

Clinical Summary— DENND3

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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

1 unique Pathogenic / Likely Pathogenic· 170 VUS of 234 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.66LOEUF

pLI 0.000

Z-score 3.65

OE 0.48 (0.36–0.66)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

2.37Z-score

OE missense 0.75 (0.70–0.81)

556 obs / 736.7 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.48 (0.36–0.66)

0≤0.351.4

Missense OE?0.75 (0.70–0.81)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 28 / 58.0Missense obs/exp: 556 / 736.7Syn Z: 0.18

ClinVar Variant Classifications

234 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic1

VUS170

Likely Benign17

Benign12

Conflicting1

Likely Pathogenic

170

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	1	0	0	0	1
VUS	0	168	0	2	170
Likely Benign	0	15	0	2	17
Benign	0	3	3	6	12
Conflicting	—				1
Total	1	186	3	10	201

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

View in ClinVar →

55 pathogenic / likely-pathogenic (of 58) ClinVar copy-number / structural variants overlap DENND3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →