# NM_000082.4(ERCC8):c.789T>A (p.Val263=)

https://sugi.bio/variant/ercc8-p-val263

## Summary

**ERCC8 p.Val263= (c.789T>A)** is classified **Likely benign** in ERCC8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-02). Very rare (popmax 0.000254%, nfe).

**At a glance:** Likely benign · review: Single submitter · rsID rs1748776795 · 1 submitter · very rare (popmax 0.000254%, nfe)

## For patients & families {#patients}

This is a change in the ERCC8 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter.

*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 | [ERCC8](https://sugi.bio/atlas/gene/ERCC8/) |
| Protein change (HGVS p.) | p.Val263= |
| Coding change (HGVS c.) | c.789T>A |
| MANE Select transcript | [NM_000082](https://www.ncbi.nlm.nih.gov/nuccore/NM_000082) |
| dbSNP | [rs1748776795](https://www.ncbi.nlm.nih.gov/snp/rs1748776795/) |
| Variant type | single nucleotide variant |
| Location | chr5:60898330-60898330 (GRCh38) |
| ClinVar | [VCV2174148](https://www.ncbi.nlm.nih.gov/clinvar/variation/2174148/) |

**All HGVS expressions:** `LRG_466:g.51749T>A`, `LRG_466t1:c.789T>A`, `NC_000005.10:g.60898330A>T`, `NC_000005.9:g.60194157A>T`, `NG_009289.1:g.51749T>A`, `NM_000082.4:c.789T>A`, `NM_001007233.3:c.615T>A`, `NM_001290285.2:c.330T>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.26) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 1.378, GERP -0.086, phastCons 0.998 — weakly conserved position
- CADD: **PHRED 16.07**. 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 deltas (raw): acceptor loss **0.02**, donor loss **0.00**, acceptor gain **0.26**, donor gain **0.08**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.26**, donor gain **0.08**.
- Population frequency (gnomAD v4.1): grpmax **0.000254%** (nfe) · FAF95 6.8e-05% · FAF99 1.9e-05% · 3/1,179,618 in the highest group · 3/1,461,336 alleles overall — very rare (popmax 0.000254%, nfe).

*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}

**ERCC8** population constraint: LOEUF 1.608, pLI 1.7192e-11, missense-Z -0.66199. *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):

- **Cockayne syndrome type 1** — Definitive (AR)

## Protein context {#protein}

Residue **263** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 91.72, 87% of residues very-high.

**16 experimental structure(s)** (PDB): [4A11](https://www.rcsb.org/structure/4A11), [6FCV](https://www.rcsb.org/structure/6FCV), [7OO3](https://www.rcsb.org/structure/7OO3), [7OOB](https://www.rcsb.org/structure/7OOB), [7OOP](https://www.rcsb.org/structure/7OOP), [7OPC](https://www.rcsb.org/structure/7OPC).

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

*Describes the biological roles of ERCC8 (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:** ERCC8's established molecular role includes ubiquitin-like ligase-substrate adaptor activity.


### Pathways affected {#pathways}

ERCC8 participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Dual incision in TC-NER](https://reactome.org/content/detail/R-HSA-6782135) | curated |
| [Formation of TC-NER Pre-Incision Complex](https://reactome.org/content/detail/R-HSA-6781823) | curated |
| [Gap-filling DNA repair synthesis and ligation in TC-NER](https://reactome.org/content/detail/R-HSA-6782210) | curated |
| [Neddylation](https://reactome.org/content/detail/R-HSA-8951664) | curated |
| [Transcription-Coupled Nucleotide Excision Repair (TC-NER)](https://reactome.org/content/detail/R-HSA-6781827) | curated |

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

**Molecular function:** ubiquitin-like ligase-substrate adaptor activity.

**Biological process:** single strand break repair, protein polyubiquitination, transcription-coupled nucleotide-excision repair, DNA damage response, response to oxidative stress, response to UV.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-09-02.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-09-02 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related ERCC8 variant pages (same residue, condition, or type): [ERCC8 c.1041+1G>T](/variant/ercc8-c-1041-plus-1g-t), [ERCC8 c.1042-2A>G](/variant/ercc8-c-1042-minus-2a-g), [ERCC8 c.173+1119G>C](/variant/ercc8-c-173-plus-1119g-c), [ERCC8 c.173+1G>A](/variant/ercc8-c-173-plus-1g-a), [ERCC8 c.275+1G>A](/variant/ercc8-c-275-plus-1g-a), [ERCC8 c.276-1G>A](/variant/ercc8-c-276-minus-1g-a), [ERCC8 c.399+1G>A](/variant/ercc8-c-399-plus-1g-a), [ERCC8 c.551-1G>A](/variant/ercc8-c-551-minus-1g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2174148). 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.*