DENND1A

Chr 9

DENN domain containing 1A

Also known as: FAM31A, KIAA1608

NCBI Gene: 57706ENSG00000119522UniProt: Q8TEH3OMIM: 613633

DENND1A encodes a guanine nucleotide exchange factor that activates RAB35 and regulates clathrin-mediated endocytosis of synaptic vesicles and exit from early endosomes. Loss-of-function mutations cause neurodevelopmental disorders with an autosomal dominant inheritance pattern due to haploinsufficiency. The protein's critical role in synaptic vesicle endocytosis explains the neurological phenotype when cellular trafficking is disrupted.

OMIMResearchSummary from RefSeq, UniProt, Mechanism
LOFmechanismLOEUF 0.23
Clinical Summary— DENND1A
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
30 unique Pathogenic / Likely Pathogenic· 154 VUS of 224 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint
0.23LOEUF
pLI 1.000
Z-score 5.60
OE 0.11 (0.06–0.23)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint
1.26Z-score
OE missense 0.85 (0.79–0.92)
493 obs / 578.3 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.11 (0.06–0.23)
0≤0.351.4
Missense OE0.85 (0.79–0.92)
0≤0.61.4
Synonymous OE1.11
0≤1.21.6
LoF obs/exp: 5 / 45.9Missense obs/exp: 493 / 578.3Syn Z: -1.37
DN
0.3892th %ile
GOF
0.5660th %ile
LOF
0.66top 25%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.23

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

224 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic29
Likely Pathogenic1
VUS154
Likely Benign7
Benign2
29
Pathogenic
1
Likely Pathogenic
154
VUS
7
Likely Benign
2
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
29
0
29
Likely Pathogenic
0
0
1
0
1
VUS
0
150
4
0
154
Likely Benign
0
5
0
2
7
Benign
0
1
0
1
2
Total0156343193

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

View in ClinVar →

Protein Context — Lollipop Plot

DENND1A · 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

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients