# NM_000124.4(ERCC6):c.1339C>T (p.Arg447Trp)

https://sugi.bio/variant/ercc6-p-arg447trp

## Summary

**ERCC6 p.Arg447Trp (c.1339C>T)** is classified **Uncertain significance** in ERCC6 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-12-02). AlphaMissense: likely benign (0.1087); Ultra-rare (popmax 0.0484%, amr).

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs200818896 · 3 submitters · AlphaMissense likely benign · ultra-rare (popmax 0.0484%, amr)

## For patients & families {#patients}

This is a change in the ERCC6 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 3 submitters.

*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 | [ERCC6](https://sugi.bio/atlas/gene/ERCC6/) |
| Protein change (HGVS p.) | p.Arg447Trp |
| Coding change (HGVS c.) | c.1339C>T |
| MANE Select transcript | [NM_000124](https://www.ncbi.nlm.nih.gov/nuccore/NM_000124) |
| dbSNP | [rs200818896](https://www.ncbi.nlm.nih.gov/snp/rs200818896/) |
| Variant type | single nucleotide variant |
| Location | chr10:49524091-49524091 (GRCh38) |
| ClinVar | [VCV2198816](https://www.ncbi.nlm.nih.gov/clinvar/variation/2198816/) |

**All HGVS expressions:** `LRG_465:g.20011C>T`, `LRG_465t1:c.1339C>T`, `NC_000010.10:g.50732137G>A`, `NC_000010.11:g.49524091G>A`, `NG_009442.1:g.20011C>T`, `NG_033155.1:g.5191C>T`, `NM_000124.4:c.1339C>T`, `NM_001277058.2:c.1339C>T`, `NM_001277059.2:c.1339C>T`, `NM_001346440.2:c.1339C>T`, `NM_170753.3:c.-66C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1087)
- REVEL 0.069 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -9.786 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 1.969, GERP 0.22, phastCons 0.014 — weakly conserved position
- CADD: **PHRED 23.6**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.60 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0484%** (amr) · FAF95 0.0345% · FAF99 0.0299% · 29/59,976 in the highest group · 224/1,613,398 alleles overall — ultra-rare (popmax 0.0484%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.0484% | 2,068 |
| Middle Eastern | 0.033% | 3,031 |
| Remaining individuals (not grpmax-eligible) | 0.0176% | 5,681 |
| European (non-Finnish) | 0.0145% | 6,900 |
| African / African-American | 0.012% | 8,316 |
| East Asian | 0.00446% | 22,435 |

*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 **447** lies in the 'disordered' region; the 'n-terminal domain; essential for its chromatin remodeling activity' region.

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.Arg447Trp falls in the disordered region.


### 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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-12-02.

**Submitter consensus:** unanimous (3/3 Uncertain significance).

**Submission history:** 3 submissions (2022–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Mayo Clinic Laboratories, Mayo Clinic | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-04-13 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-09-05 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-12-02 |

**Reported phenotype names (ClinVar):** not provided, not specified, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM, none provided, AllHighlyPenetrant.

## Similar variants {#similar}

Related ERCC6 variant pages (same residue, condition, or type): [ERCC6 p.Arg447Gln](/variant/ercc6-p-arg447gln), [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 2198816). 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.*