DENND5A

Chr 11AR

DENN domain containing 5A

Also known as: DEE49, EIEE49, RAB6IP1

NCBI Gene: 23258 ENSG00000184014 UniProt: Q6IQ26 OMIM: 617278

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.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a DENN-domain-containing protein that functions as a RAB-activating guanine nucleotide exchange factor (GEF). This protein catalyzes the conversion of GDP to GTP and thereby converts inactive GDP-bound Rab proteins into their active GTP-bound form. The encoded protein is recruited by RAB6 onto Golgi membranes and is therefore referred to as RAB6-interacting protein 1. This protein binds with RAB39 as well. Alternative splicing results in multiple transcript variants encoding distinct isoforms. Mutations in this gene are associated with early infantile epileptic encephalopathy-49. [provided by RefSeq, Feb 2017]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.381 OMIM phenotype

Clinical Summary— DENND5A

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.25) despite low pLI — interpret in context.

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ClinVar Variants

35 unique Pathogenic / Likely Pathogenic· 293 VUS of 767 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.38LOEUF

pLI 0.058

Z-score 5.61

OE 0.25 (0.17–0.38)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.38Z-score

OE missense 0.75 (0.70–0.81)

536 obs / 714.9 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.25 (0.17–0.38)

0≤0.351.4

Missense OE?0.75 (0.70–0.81)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 16 / 64.6Missense obs/exp: 536 / 714.9Syn Z: -0.15

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongDENND5A-related epileptic encephalopathyLOFAR

This gene — mechanism propensity

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

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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

767 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic18

Likely Pathogenic17

VUS293

Likely Benign397

Benign17

Conflicting8

Pathogenic

Likely Pathogenic

293

VUS

397

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	16	0	2	0	18
Likely Pathogenic	15	1	1	0	17
VUS	2	279	9	3	293
Likely Benign	1	10	144	242	397
Benign	0	3	7	7	17
Conflicting	—				8
Total	34	293	163	252	750

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

View in ClinVar →

13 pathogenic / likely-pathogenic (of 25) ClinVar copy-number / structural variants overlap DENND5A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →