DDB2

Chr 11AR

damage specific DNA binding protein 2

Also known as: DDBB, UV-DDB2, XPE

NCBI Gene: 1643 ENSG00000134574 UniProt: Q92466 OMIM: 600811

The protein functions as the DNA-binding subunit of the UV-damaged DNA-binding complex, recognizing UV-induced DNA lesions and recruiting nucleotide excision repair machinery to initiate DNA repair. Mutations cause xeroderma pigmentosum group E, an autosomal recessive disorder characterized by extreme UV sensitivity, high predisposition to skin cancer, and sometimes neurological abnormalities. The gene shows low constraint against loss-of-function variants (pLI <0.001), consistent with the recessive inheritance pattern where heterozygous carriers are typically unaffected.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a protein that is necessary for the repair of ultraviolet light-damaged DNA. This protein is the smaller subunit of a heterodimeric protein complex that participates in nucleotide excision repair, and this complex mediates the ubiquitylation of histones H3 and H4, which facilitates the cellular response to DNA damage. This subunit appears to be required for DNA binding. Mutations in this gene cause xeroderma pigmentosum complementation group E, a recessive disease that is characterized by an increased sensitivity to UV light and a high predisposition for skin cancer development, in some cases accompanied by neurological abnormalities. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2014]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Xeroderma pigmentosum, group EMIM #278740

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · xeroderma pigmentosum group E · AR · ClinGen 2019

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.85

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — DDB2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.85LOEUF

pLI 0.000

Z-score 2.11

OE 0.52 (0.33–0.85)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.22Z-score

OE missense 0.78 (0.69–0.88)

187 obs / 240.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.52 (0.33–0.85)

0≤0.351.4

Missense OE?0.78 (0.69–0.88)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 12 / 22.9Missense obs/exp: 187 / 240.1Syn Z: 0.50

Background carrier burden — how many people carry a rare variant somewhere in DDB2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 180

467 rare PASS variants

Rare truncating (LoF)

1 in 2,900

74 rare PASS variants

Rare synonymous (reference)

1 in 300

193 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for DDB2. 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 240	1 in 3,400
South Asian	~43k	1 in 210	1 in 8,600
Remaining (unassigned)	~30k	1 in 170	1 in 4,300
European (Finnish)	~27k	1 in 620	1 in 810
Admixed American	~22k	1 in 160	1 in 3,800
African / African American	~21k	1 in 160	1 in 2,600
East Asian	~20k	1 in 190	1 in 2,200
Ashkenazi Jewish	~13k	1 in 340	none seen
Middle Eastern	~2,884	1 in 170	≈ 1 in 2,900

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.