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…

Primary Disease Associations & Inheritance

Cerebrooculofacioskeletal syndrome 3MIM #616570

Xeroderma pigmentosum, group GMIM #278780

Xeroderma pigmentosum, group G/Cockayne syndromeMIM #278780

UniProtCerebro-oculo-facio-skeletal syndrome 3

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · xeroderma pigmentosum group G · AR · ClinGen 2019

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.81

LOEUF

LOF

Mechanism· G2P

📖

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

Background carrier burden — how many people carry a rare variant somewhere in ERCC5?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 33

1,475 rare PASS variants

Rare truncating (LoF)

1 in 670

229 rare PASS variants

Rare synonymous (reference)

1 in 79

582 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ERCC5. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 43	1 in 750
South Asian	~43k	1 in 36	1 in 290
Remaining (unassigned)	~30k	1 in 29	1 in 770
European (Finnish)	~27k	1 in 170	1 in 1,600
Admixed American	~22k	1 in 33	1 in 860
African / African American	~21k	1 in 33	1 in 760
East Asian	~20k	1 in 30	1 in 360
Ashkenazi Jewish	~13k	1 in 96	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 27	≈ 1 in 1,400

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 15 coding exons well covered in gnomAD exomes and genomes.? see exons ↓