# NM_000124.4(ERCC6):c.150G>A (p.Val50=)

https://sugi.bio/variant/ercc6-p-val50

## Summary

**ERCC6 p.Val50= (c.150G>A)** is classified **Conflicting classifications of pathogenicity** in ERCC6 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-27). Rare (popmax 0.151%, nfe); Associated with cerebrooculofacioskeletal syndrome 1.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs80133923 · 6 submitters · 3 linked conditions · rare (popmax 0.151%, nfe)

## 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 6 submitters, and is linked to cerebrooculofacioskeletal syndrome 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.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015150/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.Val50= |
| Coding change (HGVS c.) | c.150G>A |
| MANE Select transcript | [NM_000124](https://www.ncbi.nlm.nih.gov/nuccore/NM_000124) |
| dbSNP | [rs80133923](https://www.ncbi.nlm.nih.gov/snp/rs80133923/) |
| Variant type | single nucleotide variant |
| Location | chr10:49532815-49532815 (GRCh38) |
| ClinVar | [VCV190149](https://www.ncbi.nlm.nih.gov/clinvar/variation/190149/) |

**All HGVS expressions:** `LRG_465:g.11287G>A`, `LRG_465t1:c.150G>A`, `NC_000010.10:g.50740861C>T`, `NC_000010.11:g.49532815C>T`, `NG_009442.1:g.11287G>A`, `NM_000124.4:c.150G>A`, `NM_001277058.2:c.150G>A`, `NM_001277059.2:c.150G>A`, `NM_001346440.2:c.150G>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 0.69) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 0.198, GERP -3.82 — weakly conserved position
- CADD: **PHRED 16.4**. 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 **0.01**, donor loss **0.00**, acceptor gain **0.69**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.69**, donor gain **0.00**.
- Pangolin: Δ**0.56** (gain), gain 0.56 / loss 0.00. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.151%** (nfe) · FAF95 0.145% · FAF99 0.143% · 1,786/1,180,048 in the highest group · 1,916/1,614,222 alleles overall — rare (popmax 0.151%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.151% | 661 |
| Remaining individuals (not grpmax-eligible) | 0.109% | 919 |
| Admixed American | 0.06% | 1,667 |
| Finnish (not grpmax-eligible) | 0.0187% | 5,337 |
| African / African-American | 0.0173% | 5,774 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00338% | 29,606 |

*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 **50** lies in 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.Val50= falls in the n-terminal domain; essential for its chromatin remodeling activity 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-01-27.

**Submitter consensus:** conflicting (6 Likely benign, 2 Uncertain significance).

**Submission history:** 8 submissions (2012–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Claritas Genomics | Likely benign | criteria provided, single submitter | clinical testing | 2012-09-21 |
| Illumina Laboratory Services, Illumina | Likely benign | criteria provided, single submitter | clinical testing | 2017-04-27 |
| CeGaT Center for Human Genetics Tuebingen | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-02-01 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-27 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-12 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-08-31 |

## Associated conditions {#conditions}

[cerebrooculofacioskeletal syndrome 1](https://sugi.bio/atlas/disease/cerebrooculofacioskeletal-syndrome-1/), [age related macular degeneration 5](https://sugi.bio/atlas/disease/age-related-macular-degeneration-5/), [Cockayne syndrome type 2](https://sugi.bio/atlas/disease/cockayne-syndrome-type-2/).

**Reported phenotype names (ClinVar):** Cerebrooculofacioskeletal syndrome 1, not specified, Age related macular degeneration 5, Cockayne syndrome type 2, not provided, AllHighlyPenetrant, none provided, Cerebro-oculo-facio-skeletal syndrome 1, Cockayne Syndrome, Type II, COCKAYNE SYNDROME B.

## Similar variants {#similar}

Related ERCC6 variant pages (same residue, condition, or type): [ERCC6 p.Val50Met](/variant/ercc6-p-val50met), [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 190149). 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.*