ERCC5

Chr 13AR

ERCC excision repair 5, endonuclease

Also known as: COFS3, ERCC5-201, ERCM2, UVDR, XPG, XPGC

NCBI Gene: 2073 ENSG00000134899 UniProt: P28715 OMIM: 133530

This gene encodes a single-strand DNA endonuclease that makes the 3' incision during nucleotide excision repair following UV-induced DNA damage and is involved in transcription-coupled DNA repair. Biallelic mutations cause xeroderma pigmentosum group G, characterized by extreme UV sensitivity and increased skin cancer risk, with some patients also developing Cockayne syndrome featuring severe growth defects and intellectual disability, or the more severe cerebrooculofacioskeletal syndrome with early-onset neurodegeneration. The gene follows autosomal recessive inheritance and is highly constrained against loss-of-function variants.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a single-strand specific DNA endonuclease that makes the 3' incision in DNA excision repair following UV-induced damage. The protein may also function in other cellular processes, including RNA polymerase II transcription, and transcription-coupled DNA repair. Mutations in this gene cause xeroderma pigmentosum complementation group G (XP-G), which is also referred to as xeroderma pigmentosum VII (XP7), a skin disorder characterized by hypersensitivity to UV light and increased susceptibility for skin cancer development following UV exposure. Some patients also develop Cockayne syndrome, which is characterized by severe growth defects, cognitive disability, and cachexia. Read-through transcription exists between this gene and the neighboring upstream BIVM (basic, immunoglobulin-like variable motif containing) gene. [provided by RefSeq, Feb 2011]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.813 OMIM phenotypes

Clinical Summary— ERCC5

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Gene-Disease Validity (ClinGen)

xeroderma pigmentosum group G · 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

79 unique Pathogenic / Likely Pathogenic· 195 VUS of 553 total submissions

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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — ERCC5

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?

0.81LOEUF

pLI 0.000

Z-score 2.64

OE 0.59 (0.43–0.81)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.12Z-score

OE missense 0.99 (0.92–1.05)

628 obs / 636.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.59 (0.43–0.81)

0≤0.351.4

Missense OE?0.99 (0.92–1.05)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 28 / 47.7Missense obs/exp: 628 / 636.4Syn Z: -0.15

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveERCC5-related xeroderma pigmentosum, group GLOFAR

This gene — mechanism propensity

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

0.6551th %ile

GOF

0.3392th %ile

LOF

0.2968th %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

553 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic36

Likely Pathogenic43

VUS195

Likely Benign160

Benign60

Conflicting50

Pathogenic

Likely Pathogenic

195

VUS

160

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	31	4	1	0	36
Likely Pathogenic	34	7	2	0	43
VUS	4	165	19	7	195
Likely Benign	0	15	41	104	160
Benign	0	8	47	5	60
Conflicting	—				50
Total	69	199	110	116	544

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

View in ClinVar →

101 pathogenic / likely-pathogenic (of 111) ClinVar copy-number / structural variants overlap ERCC5 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →