DENND4B

Chr 1

DENN domain containing 4B

Also known as: KIAA0476

NCBI Gene: 9909 ENSG00000198837 UniProt: O75064 OMIM: 619843

Enables guanyl-nucleotide exchange factor activity. Involved in regulation of Rab protein signal transduction. Located in Golgi apparatus and nucleoplasm. [provided by Alliance of Genome Resources, Jul 2025]

OMIM Research

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.29

Clinical Summary— DENND4B

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 174 VUS of 242 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.29LOEUF

pLI 0.991

Z-score 6.23

OE 0.18 (0.11–0.29)

Highly constrained

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

Missense Constraint?

3.23Z-score

OE missense 0.69 (0.65–0.74)

607 obs / 876.1 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.18 (0.11–0.29)

0≤0.351.4

Missense OE?0.69 (0.65–0.74)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 12 / 67.0Missense obs/exp: 607 / 876.1Syn Z: 0.76

This gene — mechanism propensity

0.3395th %ile

GOF

0.5661th %ile

LOF

0.66top 25%

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

LOFprediction above median · LOEUF 0.29

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

242 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic1

VUS174

Likely Benign24

Benign6

Conflicting1

Likely Pathogenic

174

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	1	0	0	1
VUS	0	173	1	0	174
Likely Benign	1	1	8	14	24
Benign	0	1	0	5	6
Conflicting	—				1
Total	1	176	9	19	206

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

View in ClinVar →

16 pathogenic / likely-pathogenic (of 24) ClinVar copy-number / structural variants overlap DENND4B — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →