ERCC6

Chr 10ARADSomatic

ERCC excision repair 6, chromatin remodeling factor

NCBI Gene: 2074ENSG00000225830UniProt: Q03468

Essential factor involved in transcription-coupled nucleotide excision repair (TC-NER), a process during which RNA polymerase II-blocking lesions are rapidly removed from the transcribed strand of active genes (PubMed:16246722, PubMed:20541997, PubMed:22483866, PubMed:26620705, PubMed:32355176, PubMed:34526721, PubMed:38316879, PubMed:38600235, PubMed:38600236). Plays a central role in the initiation of the TC-NER process: specifically recognizes and binds RNA polymerase II stalled at a lesion, and mediates recruitment of ERCC8/CSA, initiating DNA damage excision by TFIIH recruitment (PubMed:32355176, PubMed:34526721, PubMed:38600235, PubMed:38600236). Upon DNA-binding, it locally modifies DNA conformation by wrapping the DNA around itself, thereby modifying the interface between stalled RNA polymerase II and DNA (PubMed:15548521). Acts as a chromatin remodeler at DSBs; DNA-dependent ATPase-dependent activity is essential for this function (PubMed:16246722, PubMed:9565609). Plays an important role in regulating the choice of the DNA double-strand breaks (DSBs) repair pathway and G2/M checkpoint activation; DNA-dependent ATPase activity is essential for this function (PubMed:25820262). Regulates the DNA repair pathway choice by inhibiting non-homologous end joining (NHEJ), thereby promoting the homologous recombination (HR)-mediated repair of DSBs during the S/G2 phases of the cell cycle (PubMed:25820262). Mediates the activation of the ATM- and CHEK2-dependent DNA damage responses thus preventing premature entry of cells into mitosis following the induction of DNA DSBs (PubMed:25820262). Remodels chromatin by evicting histones from chromatin flanking DSBs, limiting RIF1 accumulation at DSBs thereby promoting BRCA1-mediated HR (PubMed:29203878). Required for stable recruitment of ELOA and CUL5 to DNA damage sites (PubMed:28292928). Also involved in UV-induced translocation of ERCC8 to the nuclear matrix (PubMed:26620705). Essential for neuronal differentiation and neuritogenesis; regulates transcription and chromatin remodeling activities required during neurogenesis (PubMed:24874740)

Primary Disease Associations & Inheritance

?De Sanctis-Cacchione syndromeMIM #278800
AR
{Lung cancer, susceptibility to}MIM #211980
ADSomatic
{Macular degeneration, age-related, susceptibility to, 5}MIM #613761
Cerebrooculofacioskeletal syndrome 1MIM #214150
AR
Cockayne syndrome, type BMIM #133540
AR
Premature ovarian failure 11MIM #616946
AD
UV-sensitive syndrome 1MIM #600630
AR
UniProtCockayne syndrome B
UniProtCerebro-oculo-facio-skeletal syndrome 1
2175
ClinVar variants
84
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— ERCC6
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
84 Pathogenic / Likely Pathogenic· 163 VUS of 2175 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.80LOEUF
pLI 0.000
Z-score 2.96
OE 0.63 (0.49–0.80)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.10Z-score
OE missense 0.99 (0.93–1.05)
772 obs / 779.7 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.63 (0.49–0.80)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.99 (0.93–1.05)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.06
0≤1.21.6
LoF obs/exp: 46 / 73.3Missense obs/exp: 772 / 779.7Syn Z: -0.85

ClinVar Variant Classifications

2175 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic46
Likely Pathogenic38
VUS163
Likely Benign234
Benign2
Conflicting1
46
Pathogenic
38
Likely Pathogenic
163
VUS
234
Likely Benign
2
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
24
0
22
0
46
Likely Pathogenic
23
2
13
0
38
VUS
1
155
7
0
163
Likely Benign
0
5
102
127
234
Benign
0
1
1
0
2
Conflicting
—1
Total48163145127484

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

ERCC6 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

ERCC6-related Cockayne syndrome

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. DisordersEyeSkin
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

?De Sanctis-Cacchione syndrome

MIM #278800

Molecular basis of disorder known

Autosomal recessive

{Lung cancer, susceptibility to}

MIM #211980

Molecular basis of disorder known

Autosomal dominantSomatic mutation

{Macular degeneration, age-related, susceptibility to, 5}

MIM #613761

Molecular basis of disorder known

Cerebrooculofacioskeletal syndrome 1

MIM #214150

Molecular basis of disorder known

Autosomal recessive

Cockayne syndrome, type B

MIM #133540

Molecular basis of disorder known

Autosomal recessive

Premature ovarian failure 11

MIM #616946

Molecular basis of disorder known

Autosomal dominant

UV-sensitive syndrome 1

MIM #600630

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Genetic landscape of a large cohort of Primary Ovarian Insufficiency: New genes and pathways and implications for personalized medicine.
Heddar A et al.·EBioMedicine
2022Cohort
Genetic pleiotropy of ERCC6 loss-of-function and deleterious missense variants links retinal dystrophy, arrhythmia, and immunodeficiency in diverse ancestries.
Forrest IS et al.·Hum Mutat
2021Meta-analysis
Mutation update for the CSB/ERCC6 and CSA/ERCC8 genes involved in Cockayne syndrome.
Laugel V et al.·Hum Mutat
2010Meta-analysis
Novel frame shift mutation in ERCC6 leads to a severe form of Cockayne syndrome with postnatal growth failure and early death: A case report and brief literature review.
Kou Y et al.·Medicine (Baltimore)
2018Review
A novel heterozygous ERCC6 variant identified in a Chinese family with non-syndromic primary ovarian insufficiency.
Kuang L et al.·Mol Genet Genomic Med
2022
Spectrum of ERCC6-Related Cockayne Syndrome (Type B): From Mild to Severe Forms.
Sartorelli J et al.·Genes (Basel)
2024
Association of FOXL2 and ERCC6 variants with premature ovarian insufficiency and their potential use in clinical IVF guidance.
Gu M et al.·Gene
2025
Clinical and Mutation Spectra of Cockayne Syndrome in India.
Narayanan DL et al.·Neurol India
2021
Cockayne syndrome without UV-sensitivity in Vietnamese siblings with novel ERCC8 variants.
Duong NT et al.·Aging (Albany NY)
2022
Cockayne syndrome: the expanding clinical and mutational spectrum.
Laugel V·Mech Ageing Dev
2013Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Studies on the functionality of the TC-NER ERCC6-M1097V protein variant frequently found in Louisiana patients with PCa upon UV damage.
Ogundepo O et al.·Front Oncol
2025🔓 Open AccessCohort
ercc6 deficient zebrafish exhibit UV and metronidazole sensitivity, increased oxygen consumption, and impaired hair cell mechanoelectrical transduction which can be restored by the superoxide dismutase mimetic MnTBAP.
Hernandez Herrera GA et al.·Hum Mol Genet
2026Functional
A Truncating Variant in the ERCC6 Gene With Three Different Phenotypes: Significant Effects of Modifier Genes.
Khorrami M et al.·Genet Res (Camb)
2025🔓 Open Access
A Dual Approach with Organoid and CRISPR Screening Reveals ERCC6 as a Determinant of Cisplatin Resistance in Osteosarcoma.
Xu R et al.·Adv Sci (Weinh)
2025🔓 Open Access
Multiple primary tumors in a patient with non‑small‑cell lung cancer harboring mutations in ERCC6 and LYL1: A case report.
Wu H et al.·Oncol Lett
2025🔓 Open AccessCase report
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools