# NM_000082.4(ERCC8):c.812T>C (p.Leu271Pro)

https://sugi.bio/variant/ercc8-p-leu271pro

## Summary

**ERCC8 p.Leu271Pro (c.812T>C)** is classified **Uncertain significance** in ERCC8 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-12). AlphaMissense: likely pathogenic (0.9964); Very rare (popmax 0.0017%, nfe); Associated with Cockayne syndrome type 1.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs886060721 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.0017%, nfe)

## For patients & families {#patients}

This is a change in the ERCC8 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Cockayne syndrome type 1.

*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 (Europe) |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | ERCC8 is a diagnostic-grade gene on 16 Genomics England panels |

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

- Progressive microcephaly — Very frequent (99-80%)
- Progressive sensorineural hearing impairment — Very frequent (99-80%)
- Pigmentary retinopathy — Very frequent (99-80%)
- Atypical behavior — Very frequent (99-80%)
- Mental deterioration — Very frequent (99-80%)
- Cerebellar atrophy — Very frequent (99-80%)
- Growth delay — Very frequent (99-80%)
- Severe short stature — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0001415/index) · [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.Leu271Pro |
| Coding change (HGVS c.) | c.812T>C |
| MANE Select transcript | [NM_000082](https://www.ncbi.nlm.nih.gov/nuccore/NM_000082) |
| dbSNP | [rs886060721](https://www.ncbi.nlm.nih.gov/snp/rs886060721/) |
| Variant type | single nucleotide variant |
| Location | chr5:60898307-60898307 (GRCh38) |
| ClinVar | [VCV354015](https://www.ncbi.nlm.nih.gov/clinvar/variation/354015/) |

**All HGVS expressions:** `LRG_466:g.51772T>C`, `LRG_466t1:c.812T>C`, `NC_000005.10:g.60898307A>G`, `NC_000005.9:g.60194134A>G`, `NG_009289.1:g.51772T>C`, `NM_000082.4:c.812T>C`, `NM_001007233.3:c.638T>C`, `NM_001290285.2:c.353T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9964)
- REVEL 0.808 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -16.673 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 11.161, GERP 1.25, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 1%** most-pathogenic-predicted substitutions in ERCC8 (of 2,303 modeled).
- CADD: **PHRED 30.0**. 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.*
- Regional missense constraint: **o/e 1.10** across the covering region of the MANE Select transcript (60,874,618–60,945,008), spanning 70,390 bp. Chi-square p 0.027. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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 (gnomAD v4.1): grpmax **0.0017%** (nfe) · FAF95 0.00111% · FAF99 0.0009% · 20/1,179,672 in the highest group · 20/1,461,334 alleles overall — very rare (popmax 0.0017%, 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 **271** 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2018-01-12.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-12 |

## Associated conditions {#conditions}

[Cockayne syndrome type 1](https://sugi.bio/atlas/disease/cockayne-syndrome-type-1/).

**Reported phenotype names (ClinVar):** Cockayne syndrome type 1, Cockayne syndrome  type I, Cockayne syndrome classical, Cockayne syndrome classic form.

## Similar variants {#similar}

Related ERCC8 variant pages (same residue, condition, or type): [ERCC8 p.Leu271=](/variant/ercc8-p-leu271), [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).

### 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 354015). 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.*