# NM_000107.3(DDB2):c.823G>A (p.Val275Ile)

https://sugi.bio/variant/ddb2-p-val275ile

## Summary

**DDB2 p.Val275Ile (c.823G>A)** is classified **Uncertain significance** in DDB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-27). AlphaMissense: likely benign (0.0837); Very rare (popmax 0.00267%, afr); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1308275397 · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00267%, afr)

## For patients & families {#patients}

This is a change in the DDB2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Inborn genetic diseases.

*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.*

**Support & next steps:** [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.Val275Ile |
| Coding change (HGVS c.) | c.823G>A |
| MANE Select transcript | [NM_000107](https://www.ncbi.nlm.nih.gov/nuccore/NM_000107) |
| dbSNP | [rs1308275397](https://www.ncbi.nlm.nih.gov/snp/rs1308275397/) |
| Variant type | single nucleotide variant |
| Location | chr11:47234877-47234877 (GRCh38) |
| ClinVar | [VCV2286365](https://www.ncbi.nlm.nih.gov/clinvar/variation/2286365/) |

**All HGVS expressions:** `LRG_467:g.24936G>A`, `LRG_467t1:c.823G>A`, `NC_000011.10:g.47234877G>A`, `NC_000011.9:g.47256428G>A`, `NG_009365.1:g.24936G>A`, `NM_000107.3:c.823G>A`, `NM_001300734.2:c.457-2960G>A`, `NM_001399874.1:c.823G>A`, `NM_001399875.1:c.823G>A`, `NM_001399876.1:c.457-2960G>A`, `NM_001399878.1:c.631G>A`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0837)
- REVEL 0.059 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.106 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **donor loss** (Δ 0.48) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 3.872, GERP 0.022, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 15.23**. 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.*
- Regional missense constraint: **o/e 0.78** across the covering region of the MANE Select transcript (47,215,137–47,238,846), spanning 23,709 bp. Chi-square p 1.9e-07. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.48**, acceptor gain **0.10**, donor gain **0.00**. Largest is donor loss, 1 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.10**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.00267%** (afr) · FAF95 0.000443% · FAF99 0.000166% · 2/74,936 in the highest group · 2/1,614,082 alleles overall — very rare (popmax 0.00267%, afr).

*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}


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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-04-27.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-04-27 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related DDB2 variant pages (same residue, condition, or type): [DDB2 p.Glu178Ala](/variant/ddb2-p-glu178ala), [DDB2 p.Phe94Cys](/variant/ddb2-p-phe94cys), [DDB2 p.Pro27Thr](/variant/ddb2-p-pro27thr), [DDB2 p.Ser85Cys](/variant/ddb2-p-ser85cys), [DDB2 p.Ser85Tyr](/variant/ddb2-p-ser85tyr), [DDB2 p.Thr406Met](/variant/ddb2-p-thr406met), [DDB2 p.Ala301Val](/variant/ddb2-p-ala301val), [DDB2 p.Arg192Gln](/variant/ddb2-p-arg192gln).

### 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 2286365). 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.*