DCAF8

Chr 1

DDB1 and CUL4 associated factor 8

Also known as: GAN2, H326, WDR42A

NCBI Gene: 50717 ENSG00000132716 UniProt: Q5TAQ9

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.

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]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.20

Clinical Summary— DCAF8

⚡

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.

📋

ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 79 VUS of 113 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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.

ClinVar Variant Classifications

113 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic1

VUS79

Likely Benign13

Benign3

Conflicting1

Likely Pathogenic

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	1	75	2	1	79
Likely Benign	0	1	3	9	13
Benign	0	2	0	1	3
Conflicting	—				1
Total	1	79	5	11	97

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

View in ClinVar →

9 pathogenic / likely-pathogenic (of 15) ClinVar copy-number / structural variants overlap DCAF8 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →