ERCC4

Chr 16AR

ERCC excision repair 4, endonuclease catalytic subunit

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

NCBI Gene: 2072 ENSG00000175595 UniProt: Q92889 OMIM: 133520

The protein functions as a catalytic component of a structure-specific DNA repair endonuclease that makes 5-prime incisions essential for nucleotide excision repair and interstrand cross-link repair. Mutations cause autosomal recessive conditions including xeroderma pigmentosum group F, Fanconi anemia complementation group Q, Cockayne syndrome overlap disorders, and XFE progeroid syndrome, affecting DNA repair mechanisms that protect against UV damage and other genotoxic stresses. The gene shows very low constraint against loss-of-function variants, which is consistent with recessive inheritance where heterozygous carriers are typically unaffected.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.904 OMIM phenotypes

Clinical Summary— ERCC4

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Gene-Disease Validity (ClinGen)

xeroderma pigmentosum group F · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

72 unique Pathogenic / Likely Pathogenic· 560 VUS of 1036 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — ERCC4

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.90LOEUF

pLI 0.000

Z-score 2.07

OE 0.64 (0.47–0.90)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.76Z-score

OE missense 1.10 (1.02–1.18)

557 obs / 508.6 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.64 (0.47–0.90)

0≤0.351.4

Missense OE?1.10 (1.02–1.18)

0≤0.61.4

Synonymous OE?1.15

0≤1.21.6

LoF obs/exp: 25 / 39.0Missense obs/exp: 557 / 508.6Syn Z: -1.58

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongERCC4-related Fanconi anemiaLOFAR

definitiveERCC4-related xeroderma pigmentosum, group FLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6356th %ile

GOF

0.3689th %ile

LOF

0.3259th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

1036 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic36

Likely Pathogenic36

VUS560

Likely Benign290

Benign53

Conflicting47

Pathogenic

Likely Pathogenic

560

VUS

290

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	28	2	6	0	36
Likely Pathogenic	30	5	1	0	36
VUS	9	473	70	8	560
Likely Benign	1	7	87	195	290
Benign	0	1	49	3	53
Conflicting	—				47
Total	68	488	213	206	1,022

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

View in ClinVar →

15 pathogenic / likely-pathogenic (of 27) ClinVar copy-number / structural variants overlap ERCC4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →