DCAF8

Chr 1AD

DDB1 and CUL4 associated factor 8

Also known as: GAN2, H326, WDR42A

NCBI Gene: 50717 ENSG00000132716 UniProt: Q5TAQ9 OMIM: 615820

This protein functions as a substrate receptor for the CUL4-DDB1 E3 ubiquitin-protein ligase complex, which targets specific proteins for degradation. Mutations cause giant axonal neuropathy 2, a peripheral neuropathy characterized by enlarged axons, with autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants (pLI 1.0, LOEUF 0.20), indicating that complete loss of protein function is likely incompatible with normal development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a WD repeat-containing protein that interacts with the Cul4-Ddb1 E3 ligase macromolecular complex. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2009]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.201 OMIM phenotype

Clinical Summary— DCAF8

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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.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.20LOEUF

pLI 1.000

Z-score 4.85

OE 0.06 (0.03–0.20)

Highly constrained

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

Missense Constraint?

3.15Z-score

OE missense 0.53 (0.47–0.60)

191 obs / 359.2 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.06 (0.03–0.20)

0≤0.351.4

Missense OE?0.53 (0.47–0.60)

0≤0.61.4

Synonymous OE?0.84

0≤1.21.6

LoF obs/exp: 2 / 31.3Missense obs/exp: 191 / 359.2Syn Z: 1.38

This gene — mechanism propensity

0.3991th %ile

GOF

0.3590th %ile

LOF

0.69top 10%

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

LOFprediction above median · LOEUF 0.20

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.