DENND4C

Chr 9

DENN domain containing 4C

Also known as: C9orf55, C9orf55B, RAB10GEF, bA513M16.3

NCBI Gene: 55667ENSG00000137145UniProt: Q5VZ89

The protein functions as a guanine nucleotide exchange factor that activates RAB10 and promotes insulin-stimulated glucose transporter delivery to the plasma membrane. Mutations cause autosomal recessive developmental and epileptic encephalopathy with microcephaly, which presents in early infancy with severe epilepsy, developmental delay, and progressive microcephaly. The gene shows high intolerance to loss-of-function variation, indicating that complete protein loss is likely incompatible with normal development.

ResearchSummary from RefSeq, UniProt
DNmechanismLOEUF 0.45
Clinical Summary— DENND4C
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.32) despite low pLI — interpret in context.
📋
ClinVar Variants
79 unique Pathogenic / Likely Pathogenic· 281 VUS of 412 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
0.45LOEUF
pLI 0.000
Z-score 5.60
OE 0.32 (0.23–0.45)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
-0.65Z-score
OE missense 1.06 (1.00–1.12)
926 obs / 872.2 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios
LoF OE0.32 (0.23–0.45)
0≤0.351.4
Missense OE1.06 (1.00–1.12)
0≤0.61.4
Synonymous OE1.14
0≤1.21.6
LoF obs/exp: 25 / 78.5Missense obs/exp: 926 / 872.2Syn Z: -1.98
DN
0.6259th %ile
GOF
0.5465th %ile
LOF
0.4136th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

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

ClinVar Variant Classifications

412 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic74
Likely Pathogenic5
VUS281
Likely Benign15
74
Pathogenic
5
Likely Pathogenic
281
VUS
15
Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
74
0
74
Likely Pathogenic
0
0
5
0
5
VUS
1
266
14
0
281
Likely Benign
0
7
6
2
15
Benign
0
0
0
0
0
Total1273992375

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

View in ClinVar →

Protein Context — Lollipop Plot

DENND4C · 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 ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Circular RNA DENND4C Regulates Cell Malignant Behaviors in Breast Cancer Through the miR-26a-5p/HSPA8 Axis.
Guo M et al.·Breast Cancer (Dove Med Press)
2025Open Access
Circ DENND4C inhibits pyroptosis and alleviates ischemia-reperfusion acute kidney injury by exosomes secreted from human urine-derived stem cells.
Yang B et al.·Chem Biol Interact
2024
Circular RNA-DENND4C in H9c2 cells relieves OGD/R-induced injury by down regulation of microRNA-320.
Zhang J et al.·Cell Cycle
2020
Circ-DENND4C up-regulates TCF4 expression to modulate hepatocellular carcinoma cell proliferation and apoptosis via activating Wnt/β-catenin signal pathway.
Liu X et al.·Cancer Cell Int
2020Open Access
Insulin-stimulated GLUT4 protein translocation in adipocytes requires the Rab10 guanine nucleotide exchange factor Dennd4C.
Sano H et al.·J Biol Chem
2011
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