# NM_000124.4(ERCC6):c.2054T>C (p.Leu685Pro)

https://sugi.bio/variant/ercc6-p-leu685pro

## Summary

**ERCC6 p.Leu685Pro (c.2054T>C)** is classified **Conflicting classifications of pathogenicity** in ERCC6 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2022-08-12). AlphaMissense: likely pathogenic (0.9992); Absent from gnomAD v4.1; Associated with Cockayne syndrome type 2.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs1275257135 · 2 submitters · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the ERCC6 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters, and is linked to Cockayne syndrome type 2.

*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) |
| Diagnostic panels | ERCC6 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/0001420/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ERCC6](https://sugi.bio/atlas/gene/ERCC6/) |
| Protein change (HGVS p.) | p.Leu685Pro |
| Coding change (HGVS c.) | c.2054T>C |
| MANE Select transcript | [NM_000124](https://www.ncbi.nlm.nih.gov/nuccore/NM_000124) |
| dbSNP | [rs1275257135](https://www.ncbi.nlm.nih.gov/snp/rs1275257135/) |
| Variant type | single nucleotide variant |
| Location | chr10:49482802-49482802 (GRCh38) |
| ClinVar | [VCV1973627](https://www.ncbi.nlm.nih.gov/clinvar/variation/1973627/) |

**All HGVS expressions:** `LRG_465:g.61300T>C`, `LRG_465t1:c.2054T>C`, `NC_000010.10:g.50690848A>G`, `NC_000010.11:g.49482802A>G`, `NG_009442.1:g.61300T>C`, `NM_000124.4:c.2054T>C`, `NM_001346440.2:c.2054T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9992)
- REVEL 0.979 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -14.976 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 11.191, GERP 1.9, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 1%** most-pathogenic-predicted substitutions in ERCC6 (of 8,762 modeled).
- CADD: **PHRED 29.2**. 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 0.94** across the covering region of the MANE Select transcript (49,458,818–49,532,964), spanning 74,146 bp. Chi-square p 0.017. 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: **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}

**ERCC6** population constraint: LOEUF 0.803, pLI 1.2087e-23, missense-Z 1.7245. *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 spectrum with or without cerebrooculofacioskeletal syndrome** — Definitive (AR)

## Protein context {#protein}

Residue **685** lies in the helicase atp-binding domain; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 70.12, 32% of residues very-high.

**12 experimental structure(s)** (PDB): [4CVO](https://www.rcsb.org/structure/4CVO), [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), [7OPD](https://www.rcsb.org/structure/7OPD).

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

*Describes the biological roles of ERCC6 (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:** ERCC6's established molecular role includes sequence-specific DNA binding. p.Leu685Pro falls in the helicase atp-binding domain.


### Pathways affected {#pathways}

ERCC6 participates in **7 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [B-WICH complex positively regulates rRNA expression](https://reactome.org/content/detail/R-HSA-5250924) | curated |
| [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 |
| [RNA Polymerase I Transcription Initiation](https://reactome.org/content/detail/R-HSA-73762) | curated |
| [Transcription-Coupled Nucleotide Excision Repair (TC-NER)](https://reactome.org/content/detail/R-HSA-6781827) | curated |
| [ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression](https://reactome.org/content/detail/R-HSA-427389) | electronic |

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

**Molecular function:** sequence-specific DNA binding, DNA binding, chromatin binding, ATP binding, ATP-dependent activity, acting on DNA, protein tyrosine kinase activator activity.

**Biological process:** positive regulation of defense response to virus by host, positive regulation of gene expression, positive regulation of peptidyl-serine phosphorylation of STAT protein, positive regulation of DNA repair, single strand break repair, DNA damage checkpoint signaling.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2022-08-12.

**Submitter consensus:** conflicting (1 Uncertain significance, 1 Likely pathogenic).

**Submission history:** 2 submissions (2022); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-08-12 |
| Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin | Likely pathogenic | criteria provided, single submitter | not provided |  |

## Associated conditions {#conditions}

[Cockayne syndrome type 2](https://sugi.bio/atlas/disease/cockayne-syndrome-type-2/).

**Reported phenotype names (ClinVar):** Cockayne syndrome type 2, not provided, Cockayne Syndrome, Type II, COCKAYNE SYNDROME B, none provided.

## Similar variants {#similar}

Related ERCC6 variant pages (same residue, condition, or type): [ERCC6 p.Leu685=](/variant/ercc6-p-leu685), [ERCC6 c.1397+1G>C](/variant/ercc6-c-1397-plus-1g-c), [ERCC6 c.1526+1G>T](/variant/ercc6-c-1526-plus-1g-t), [ERCC6 c.2169+1G>A](/variant/ercc6-c-2169-plus-1g-a), [ERCC6 c.2170-1G>A](/variant/ercc6-c-2170-minus-1g-a), [ERCC6 c.2286+1G>A](/variant/ercc6-c-2286-plus-1g-a), [ERCC6 c.2287-2A>G](/variant/ercc6-c-2287-minus-2a-g), [ERCC6 c.2599-26A>G](/variant/ercc6-c-2599-minus-26a-g).

### 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 1973627). 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.*