ERCC4

Chr 16AR

ERCC excision repair 4, endonuclease catalytic subunit

Also known as: ERCC11, FANCQ, RAD1, XFEPS, XPF

NCBI Gene: 2072ENSG00000175595UniProt: Q92889

The protein encoded by this gene forms a complex with ERCC1 and is involved in the 5' incision made during nucleotide excision repair. This complex is a structure specific DNA repair endonuclease that interacts with EME1. Defects in this gene are a cause of xeroderma pigmentosum complementation group F (XP-F), or xeroderma pigmentosum VI (XP6).[provided by RefSeq, Mar 2009]

Primary Disease Associations & Inheritance

Fanconi anemia, complementation group QMIM #615272
AR
Xeroderma pigmentosum, group FMIM #278760
AR
Xeroderma pigmentosum, type F/Cockayne syndromeMIM #278760
AR
XFE progeroid syndromeMIM #610965
AR
UniProtFanconi anemia complementation group Q
649
ClinVar variants
60
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— ERCC4
🧬
Gene-Disease Validity (ClinGen)
xeroderma pigmentosum group F · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
60 Pathogenic / Likely Pathogenic· 370 VUS of 649 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.
0.90LOEUF
pLI 0.000
Z-score 2.07
OE 0.64 (0.47–0.90)
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.
-0.76Z-score
OE missense 1.10 (1.02–1.18)
557 obs / 508.6 exp
Tolerant

Tolerant to missense variation

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.0.64 (0.47–0.90)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.10 (1.02–1.18)
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.1.15
0≤1.21.6
LoF obs/exp: 25 / 39.0Missense obs/exp: 557 / 508.6Syn Z: -1.58

ClinVar Variant Classifications

649 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic36
Likely Pathogenic24
VUS370
Likely Benign172
Benign11
Conflicting36
36
Pathogenic
24
Likely Pathogenic
370
VUS
172
Likely Benign
11
Benign
36
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
7
2
27
0
36
Likely Pathogenic
15
3
6
0
24
VUS
6
311
49
4
370
Likely Benign
1
7
49
115
172
Benign
0
1
8
2
11
Conflicting
—36
Total29324139121649

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

View in ClinVar →

Protein Context — Lollipop Plot

ERCC4 · protein map & ClinVar variants

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

Gene2Phenotype Curations

ERCC4-related Fanconi anemia

strong
ARLoss Of FunctionAbsent Gene Product
Dev. DisordersCancer
G2P ↗

ERCC4-related xeroderma pigmentosum, group F

definitive
ARLoss Of FunctionAbsent Gene Product
Skin
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Fanconi anemia, complementation group Q

MIM #615272

Molecular basis of disorder known

Autosomal recessive

Xeroderma pigmentosum, group F

MIM #278760

Molecular basis of disorder known

Autosomal recessive

Xeroderma pigmentosum, type F/Cockayne syndrome

MIM #278760

Molecular basis of disorder known

Autosomal recessive

XFE progeroid syndrome

MIM #610965

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — ERCC4
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Frequency of Pathogenic Germline Variants in Cancer-Susceptibility Genes in the Childhood Cancer Survivor Study.
Kim J et al.·JNCI Cancer Spectr
2021
Assessing the Pathogenicity, Penetrance, and Expressivity of Putative Disease-Causing Variants in a Population Setting.
Wright CF et al.·Am J Hum Genet
2019
Cancer-associated fibroblast derived CXCL14 drives cisplatin chemoresistance by enhancing nucleotide excision repair in bladder cancer.
Li T et al.·J Exp Clin Cancer Res
2025
Prevalence of germline variants in Brazilian pancreatic carcinoma patients.
Rodrigues LM et al.·Sci Rep
2024Cohort
Pathogenic variants reveal candidate genes for prostate cancer germline testing for men of African ancestry.
Gheybi K et al.·Nat Commun
2025
Heterogeneity and overlaps in nucleotide excision repair disorders.
Ferri D et al.·Clin Genet
2020Review
Gene-Level Associations in Patients With and Without Pathogenic Germline Variants in CDKN2A and Pancreatic Cancer.
Astiazaran-Symonds E et al.·JCO Precis Oncol
2022Cohort
Unveiling Secondary Mutations in Blended Phenotypes: Dual ERCC4 and OTOA Pathogenic Variants Through WES Analysis.
Failla P et al.·Int J Mol Sci
2024
An ERCC4 regulatory variant predicts grade-3 or -4 toxicities in patients with advanced non-small cell lung cancer treated by platinum-based therapy.
Zhang R et al.·Int J Cancer
2018Cohort
Cerebellar ataxia-dominant phenotype in patients with ERCC4 mutations.
Doi H et al.·J Hum Genet
2018Case report
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
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