DEPDC5

Chr 22ARAD

DEP domain containing 5, GATOR1 subcomplex subunit

Also known as: DEE111, DEP.5, FFEVF, FFEVF1, FPEVF

NCBI Gene: 9681ENSG00000100150UniProt: O75140

This gene encodes a member of the IML1 family of proteins involved in G-protein signaling pathways. The mechanistic target of rapamycin complex 1 (mTORC1) pathway regulates cell growth by sensing the availability of nutrients. The protein encoded by this gene is a component of the GATOR1 (GAP activity toward Rags) complex which inhibits the amino acid-sensing branch of the mTORC1 pathway. Mutations in this gene are associated with autosomal dominant familial focal epilepsy with variable foci. A single nucleotide polymorphism in an intron of this gene has been associated with an increased risk of hepatocellular carcinoma in individuals with chronic hepatitis C virus infection. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2014]

Primary Disease Associations & Inheritance

Developmental and epileptic encephalopathy 111MIM #620504
AR
Epilepsy, familial focal, with variable foci 1MIM #604364
AD
2814
ClinVar variants
82
Pathogenic / LP
0.12
pLI score
1
Active trials
Clinical Summary— DEPDC5
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.24) despite low pLI — interpret in context.
📋
ClinVar Variants
82 Pathogenic / Likely Pathogenic· 243 VUS of 2814 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.33LOEUF
pLI 0.116
Z-score 7.15
OE 0.24 (0.17–0.33)
Highly constrained

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

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
2.65Z-score
OE missense 0.76 (0.71–0.81)
713 obs / 941.9 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.24 (0.17–0.33)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.76 (0.71–0.81)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.94
0≤1.21.6
LoF obs/exp: 24 / 102.0Missense obs/exp: 713 / 941.9Syn Z: 0.84

ClinVar Variant Classifications

2814 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic50
Likely Pathogenic32
VUS243
Likely Benign137
Benign2
50
Pathogenic
32
Likely Pathogenic
243
VUS
137
Likely Benign
2
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
29
0
21
0
50
Likely Pathogenic
26
0
6
0
32
VUS
3
217
21
2
243
Likely Benign
0
2
75
60
137
Benign
0
1
1
0
2
Total5822012462464

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

View in ClinVar →

Protein Context — Lollipop Plot

DEPDC5 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

DEPDC5-related familial focal epilepsy with variable foci

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Developmental and epileptic encephalopathy 111

MIM #620504

Molecular basis of disorder known

Autosomal recessive

Epilepsy, familial focal, with variable foci 1

MIM #604364

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
DEPDC5-related epilepsy: A comprehensive review.
Samanta D·Epilepsy Behav
2022Review
The landscape of epilepsy-related GATOR1 variants.
Baldassari S et al.·Genet Med
2019
Dissecting the genetic basis of focal cortical dysplasia: a large cohort study.
Baldassari S et al.·Acta Neuropathol
2019Cohort
Insights Into DEPDC5-Related Epilepsy From 586 People: Variant Penetrance, Phenotypic Spectrum, and Treatment Outcomes.
Ochoa-Urrea M et al.·Neurology
2025
DEPDC5 plays a vital role in epilepsy: Genotypic and phenotypic features in cohort and literature.
Gu C et al.·Epileptic Disord
2024Review
Widespread genomic influences on phenotype in Dravet syndrome, a 'monogenic' condition.
Martins Custodio H et al.·Brain
2023
Somatic variant analysis of resected brain tissue in epilepsy surgery patients.
Sanders MWCB et al.·Epilepsia
2024Cohort
Genotypic and clinical phenotypic analysis of DEPDC5 gene mutations.
Li B et al.·Neurogenetics
2025
The clinical, imaging, pathological and genetic landscape of bottom-of-sulcus dysplasia.
Macdonald-Laurs E et al.·Brain
2024
Cardiac Investigations in Sudden Unexpected Death in DEPDC5-Related Epilepsy.
Bacq A et al.·Ann Neurol
2022
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Epilepsy

Precision Medicine in the Treatment of Epilepsy

RECRUITING
NCT05450822Gitte Moos KnudsenStarted 2022-02-18
LevetiracetamLevetiracetam TabletsLamotrigine tablet

External Resources

Links to major genomics databases and tools