DDB1

Chr 11AD

damage specific DNA binding protein 1

Also known as: DDBA, UV-DDB1, WHIKERS, XAP1, XPCE, XPE, XPE-BF

NCBI Gene: 1642 ENSG00000167986 UniProt: Q16531 OMIM: 600045

DDB1 encodes the large subunit of the UV-damaged DNA-binding complex that recognizes UV-induced DNA damage and initiates nucleotide excision repair, and also functions as an adaptor for cullin 4 ubiquitin ligase complexes that regulate protein degradation. Mutations cause White-Kernohan syndrome with autosomal dominant inheritance. This gene is highly constrained against loss-of-function variants (pLI 0.9997, LOEUF 0.243), indicating that most loss-of-function mutations are likely pathogenic.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is the large subunit (p127) of the heterodimeric DNA damage-binding (DDB) complex while another protein (p48) forms the small subunit. This protein complex functions in nucleotide-excision repair and binds to DNA following UV damage. Defective activity of this complex causes the repair defect in patients with xeroderma pigmentosum complementation group E (XPE) - an autosomal recessive disorder characterized by photosensitivity and early onset of carcinomas. However, it remains for mutation analysis to demonstrate whether the defect in XPE patients is in this gene or the gene encoding the small subunit. In addition, Best vitelliform mascular dystrophy is mapped to the same region as this gene on 11q, but no sequence alternations of this gene are demonstrated in Best disease patients. The protein encoded by this gene also functions as an adaptor molecule for the cullin 4 (CUL4) ubiquitin E3 ligase complex by facilitating the binding of substrates to this complex and the ubiquitination of proteins. [provided by RefSeq, May 2012]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

White-Kernohan syndromeMIM #619426

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists White-Kernohan syndrome; no ClinGen or GenCC tier

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

106

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.24

LOEUF· LoF intol.

LOF

Mechanism· predicted

📖

GeneReview available — DDB1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.24LOEUF

pLI 1.000

Z-score 6.19

OE 0.13 (0.08–0.24)

Highly constrained

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

Missense Constraint?

4.89Z-score

OE missense 0.47 (0.43–0.51)

313 obs / 668.5 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.13 (0.08–0.24)

0≤0.351.4

Missense OE?0.47 (0.43–0.51)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 8 / 59.5Missense obs/exp: 313 / 668.5Syn Z: -0.59

Background carrier burden — how many people carry a rare variant somewhere in DDB1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 130

910 rare PASS variants

Rare truncating (LoF)

1 in 6,300

50 rare PASS variants

Rare synonymous (reference)

1 in 90

622 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for DDB1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 160	1 in 7,500
South Asian	~43k	1 in 130	none seen
Remaining (unassigned)	~30k	1 in 80	1 in 6,000
European (Finnish)	~27k	1 in 190	≈ 1 in 8,900
Admixed American	~22k	1 in 160	1 in 950
African / African American	~21k	1 in 140	≈ 1 in 21,000
East Asian	~20k	1 in 110	≈ 1 in 9,900
Ashkenazi Jewish	~13k	1 in 320	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 96	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 26 of 27 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: all 27.? see exons ↓