DCUN1D3

Chr 16

defective in cullin neddylation 1 domain containing 3

Also known as: 44M2.4, DCNL3, SCCRO3

NCBI Gene: 123879 ENSG00000188215 UniProt: Q8IWE4 OMIM: 616167

The protein facilitates neddylation of cullin proteins, which regulates SCF ubiquitin E3 ligase complexes involved in cell cycle progression and DNA damage response. Mutations cause autosomal dominant developmental delay with seizures and dysmorphic features, typically presenting in infancy or early childhood. The gene is highly constrained against loss-of-function variants (pLI = 0.87, LOEUF = 0.43), consistent with its essential role in cellular regulation.

OMIM ResearchSummary from RefSeq, UniProt

Enables cullin family protein binding activity. Involved in several processes, including negative regulation of G1/S transition of mitotic cell cycle; regulation of protein neddylation; and response to UV-C. Located in several cellular components, including cytosol; nucleoplasm; and perinuclear region of cytoplasm. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

GOFmechanismLOEUF 0.43

Clinical Summary— DCUN1D3

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.87) — some intolerance to loss-of-function variants.

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ClinVar Variants

31 VUS of 38 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?

0.43LOEUF

pLI 0.867

Z-score 2.79

OE 0.09 (0.03–0.43)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.40Z-score

OE missense 0.70 (0.60–0.81)

119 obs / 170.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.09 (0.03–0.43)

0≤0.351.4

Missense OE?0.70 (0.60–0.81)

0≤0.61.4

Synonymous OE?0.91

0≤1.21.6

LoF obs/exp: 1 / 11.0Missense obs/exp: 119 / 170.4Syn Z: 0.57

This gene — mechanism propensity

0.3395th %ile

GOF

0.6443th %ile

LOF

0.60top 25%

The highest-scoring mechanism for this gene is gain-of-function.

GOFprediction 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

38 submitted variants in ClinVar

ClinVar

Classification Summary

VUS31

VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	31	31
Likely Benign	0	0
Benign	0	0
Total	31	31

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

View in ClinVar →

14 pathogenic / likely-pathogenic (of 20) ClinVar copy-number / structural variants overlap DCUN1D3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →