# NM_000107.3(DDB2):c.937C>T (p.Arg313Ter)

https://sugi.bio/variant/ddb2-p-arg313ter

## Summary

**DDB2 p.Arg313Ter (c.937C>T)** is classified **Pathogenic** in DDB2 (ClinVar, Single submitter, 2 submitters; last evaluated 2021-10-12). Absent from gnomAD v4.1; Associated with xeroderma pigmentosum group E.

**At a glance:** Pathogenic · review: Single submitter · rsID rs121434641 · 2 submitters · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the DDB2 gene that is reported as disease-causing, but on limited review, submitted by 2 submitters, and is linked to xeroderma pigmentosum group E.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | All ages |
| Prevalence | 1-9 / 1 000 000 (United States) |
| Diagnostic panels | DDB2 is a diagnostic-grade gene on 8 Genomics England panels |

**Commonly reported features of Xeroderma pigmentosum** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Hypogonadism — Very frequent (99-80%)
- Abnormality of the dentition — Very frequent (99-80%)
- Conjunctival telangiectasia — Very frequent (99-80%)
- Optic atrophy — Very frequent (99-80%)
- Dry skin — Very frequent (99-80%)
- Thin skin — Very frequent (99-80%)
- Cutaneous photosensitivity — Very frequent (99-80%)
- Telangiectasia — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0005627/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DDB2](https://sugi.bio/atlas/gene/DDB2/) |
| Protein change (HGVS p.) | p.Arg313Ter |
| Coding change (HGVS c.) | c.937C>T |
| MANE Select transcript | [NM_000107](https://www.ncbi.nlm.nih.gov/nuccore/NM_000107) |
| dbSNP | [rs121434641](https://www.ncbi.nlm.nih.gov/snp/rs121434641/) |
| Variant type | single nucleotide variant |
| Location | chr11:47235326-47235326 (GRCh38) |
| ClinVar | [VCV8789](https://www.ncbi.nlm.nih.gov/clinvar/variation/8789/) |

**All HGVS expressions:** `LRG_467:g.25385C>T`, `NC_000011.10:g.47235326C>T`, `NC_000011.9:g.47256877C>T`, `NG_009365.1:g.25385C>T`, `NM_000107.3:c.937C>T`, `NM_001300734.2:c.457-2511C>T`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 3.977, GERP 2.18, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.719, pLI 0.00014594. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 7 of 10**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 40.0**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**DDB2** population constraint: LOEUF 0.719, pLI 0.00014594, missense-Z 2.2896; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **xeroderma pigmentosum group E** — Definitive (AR)

## Protein context {#protein}

Residue **313** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 83.69, 70% of residues very-high.

**10 experimental structure(s)** (PDB): [3EI4](https://www.rcsb.org/structure/3EI4), [3I7L](https://www.rcsb.org/structure/3I7L), [4E54](https://www.rcsb.org/structure/4E54), [4E5Z](https://www.rcsb.org/structure/4E5Z), [6R8Y](https://www.rcsb.org/structure/6R8Y), [6R8Z](https://www.rcsb.org/structure/6R8Z).

## What this gene does {#gene-function}

*Describes the biological roles of DDB2 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** DDB2's established molecular role includes protein-containing complex binding.


### Pathways affected {#pathways}

DDB2 participates in **6 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [DNA Damage Recognition in GG-NER](https://reactome.org/content/detail/R-HSA-5696394) | curated |
| [Dual Incision in GG-NER](https://reactome.org/content/detail/R-HSA-5696400) | curated |
| [Formation of Incision Complex in GG-NER](https://reactome.org/content/detail/R-HSA-5696395) | curated |
| [Neddylation](https://reactome.org/content/detail/R-HSA-8951664) | curated |
| [TP53 Regulates Transcription of DNA Repair Genes](https://reactome.org/content/detail/R-HSA-6796648) | curated |
| [Ub-specific processing proteases](https://reactome.org/content/detail/R-HSA-5689880) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** protein-containing complex binding.

**Biological process:** protein polyubiquitination, nucleotide-excision repair, DNA damage response, response to UV, cellular response to UV, protein autoubiquitination.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-10-12.

**Submitter consensus:** unanimous (2/2 Pathogenic).

**Submission history:** 2 submissions (1999–2021); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2021-10-12 |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 1999-08-01 |

## Associated conditions {#conditions}

[xeroderma pigmentosum group E](https://sugi.bio/atlas/disease/xeroderma-pigmentosum-group-e/).

**Reported phenotype names (ClinVar):** Xeroderma pigmentosum, group E, Xeroderma pigmentosum, group E, DDB-negative subtype, Xeroderma pigmentosum, complementation group E, DDB-negative form, XERODERMA PIGMENTOSUM V, XP, GROUP E, DDB2-Related Xeroderma Pigmentosum, Xeroderma pigmentosum, complementation group E.

## Similar variants {#similar}

Related DDB2 variant pages (same residue, condition, or type): [DDB2 p.Arg313Gln](/variant/ddb2-p-arg313gln), [DDB2 c.702+1G>T](/variant/ddb2-c-702-plus-1g-t), [DDB2 p.Arg273His](/variant/ddb2-p-arg273his), [DDB2 p.Glu178Ala](/variant/ddb2-p-glu178ala), [DDB2 p.Phe94Cys](/variant/ddb2-p-phe94cys), [DDB2 p.Pro357Leu](/variant/ddb2-p-pro357leu), [DDB2 p.Ser85Cys](/variant/ddb2-p-ser85cys), [DDB2 p.Val263Ile](/variant/ddb2-p-val263ile).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 8789). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*