DENND5A

Chr 11AR

DENN domain containing 5A

Also known as: DEE49, EIEE49, RAB6IP1

The protein functions as a guanine nucleotide exchange factor that activates Rab proteins by catalyzing GDP to GTP conversion and is recruited by RAB6 to Golgi membranes where it regulates membrane trafficking. Biallelic loss-of-function mutations cause developmental and epileptic encephalopathy 49, inherited in an autosomal recessive pattern. The pathogenic mechanism involves gain-of-function effects that disrupt normal Golgi-mediated cellular processes.

OMIMResearchSummary from RefSeq, OMIM, UniProt, Mechanism
LOFmechanismARLOEUF 0.381 OMIM phenotype
Clinical SummaryDENND5A
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.25) despite low pLI — interpret in context.

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Moderate LoF intolerance
LoF Constraint
0.38LOEUF
pLI 0.058
Z-score 5.61
OE 0.25 (0.170.38)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
2.38Z-score
OE missense 0.75 (0.700.81)
536 obs / 714.9 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios
LoF OE0.25 (0.170.38)
00.351.4
Missense OE0.75 (0.700.81)
00.61.4
Synonymous OE1.01
01.21.6
LoF obs/exp: 16 / 64.6Missense obs/exp: 536 / 714.9Syn Z: -0.15
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
strongDENND5A-related epileptic encephalopathyLOFAR

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

DN
0.5967th %ile
GOF
0.6541th %ile
LOF
0.3647th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

0 submitted variants in ClinVar

Protein Context — Lollipop Plot

DENND5A · 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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