UV-sensitive syndrome 2

Summary

UV-sensitive syndrome 2 (MONDO:0013829) is a disease caused by ERCC8 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: ERCC8 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 36

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	UV-sensitive syndrome 2
Mondo ID	MONDO:0013829
OMIM	614621
NCIT	C173110
UMLS	C3553298
MedGen	766212
GARD	0015827
Is cancer (heuristic)	no

Also known as: ERCC8 UV-sensitive syndrome · UV-sensitive syndrome 2 · UV-sensitive syndrome caused by mutation in ERCC8 · UV-sensitive syndrome type 2 · UVSS2

Data availability: 36 ClinVar variants · 1 GenCC gene-disease record · 1 cell line.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › UV-sensitive syndrome › UV-sensitive syndrome 2

Related subtypes (2): UV-sensitive syndrome 1, UV-sensitive syndrome 3

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

36 retrieved; paginated sample, class counts are floors:

16 pathogenic/likely pathogenic, 8 likely pathogenic, 6 pathogenic, 3 conflicting classifications of pathogenicity, 1 likely benign, 1 benign, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
1075397	NM_000082.4(ERCC8):c.1041+1G>T	ERCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1364013	NM_000082.4(ERCC8):c.174C>A (p.Tyr58Ter)	ERCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1388419	NM_000082.4(ERCC8):c.162del (p.Glu55fs)	ERCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1455112	NM_000082.4(ERCC8):c.223_227del (p.Asn75fs)	ERCC8	Pathogenic	criteria provided, multiple submitters, no conflicts
1716	NM_000082.4(ERCC8):c.37G>T (p.Glu13Ter)	ERCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1718	NM_000082.4(ERCC8):c.613G>C (p.Ala205Pro)	ERCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2795688	NM_000082.4(ERCC8):c.378del (p.Trp127fs)	ERCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2982172	NM_000082.4(ERCC8):c.467_468dup (p.Cys157fs)	ERCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3000695	NM_000082.4(ERCC8):c.547C>T (p.Gln183Ter)	ERCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3340048	NM_000082.4(ERCC8):c.176T>C (p.Met59Thr)	ERCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3592728	NM_000082.4(ERCC8):c.370_371del (p.Leu124fs)	ERCC8	Pathogenic	criteria provided, single submitter
3592731	NM_000082.4(ERCC8):c.2T>G (p.Met1Arg)	ERCC8	Pathogenic	criteria provided, single submitter
371025	NM_000082.4(ERCC8):c.300C>G (p.Tyr100Ter)	ERCC8	Pathogenic	criteria provided, multiple submitters, no conflicts
551068	NM_000082.4(ERCC8):c.618-1G>A	ERCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
551594	NM_000082.4(ERCC8):c.1042-2A>G	ERCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
553300	NM_000082.4(ERCC8):c.600dup (p.Ile201fs)	ERCC8	Pathogenic	criteria provided, multiple submitters, no conflicts
590788	NM_000082.4(ERCC8):c.769G>A (p.Gly257Arg)	ERCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
645783	NM_000082.4(ERCC8):c.481G>A (p.Val161Ile)	ERCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
68752	NM_000082.4(ERCC8):c.1083G>T (p.Trp361Cys)	ERCC8	Pathogenic	no assertion criteria provided
68756	NM_000082.4(ERCC8):c.797A>G (p.Asp266Gly)	ERCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
838966	NM_000082.4(ERCC8):c.802C>T (p.Arg268Ter)	ERCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
984264	NM_000082.4(ERCC8):c.182C>G (p.Ser61Ter)	ERCC8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3592723	NM_000082.4(ERCC8):c.1101del (p.Glu367fs)	ERCC8	Likely pathogenic	criteria provided, single submitter
3592724	NM_000082.4(ERCC8):c.968C>G (p.Ser323Ter)	ERCC8	Likely pathogenic	criteria provided, single submitter
3592725	NM_000082.4(ERCC8):c.718+2T>C	ERCC8	Likely pathogenic	criteria provided, single submitter
3592726	NM_000082.4(ERCC8):c.668del (p.Cys222_Leu223insTer)	ERCC8	Likely pathogenic	criteria provided, single submitter
3592727	NM_000082.4(ERCC8):c.482-1G>T	ERCC8	Likely pathogenic	criteria provided, single submitter
3592729	NM_000082.4(ERCC8):c.68C>G (p.Ser23Ter)	ERCC8	Likely pathogenic	criteria provided, single submitter
3592730	NM_000082.4(ERCC8):c.9del (p.Leu5fs)	ERCC8	Likely pathogenic	criteria provided, single submitter
68753	NM_000082.4(ERCC8):c.478G>A (p.Ala160Thr)	ERCC8	Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 4 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
ERCC8	Strong	Autosomal recessive	UV-sensitive syndrome 2	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ERCC8	Orphanet:178338	UV-sensitive syndrome
ERCC8	Orphanet:90321	Cockayne syndrome type 1
ERCC8	Orphanet:90322	Cockayne syndrome type 2
ERCC8	Orphanet:90324	Cockayne syndrome type 3

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ERCC8	HGNC:3439	ENSG00000049167	Q13216	DNA excision repair protein ERCC-8	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ERCC8	DNA excision repair protein ERCC-8	Substrate-recognition component of the CSA complex, a DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complex, involved in transcription-coupled nucleotide excision repair (TC-NER), a process during which RNA polymerase II-blocking lesio…

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Scaffold/PPI	1	17.3×	0.058

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ERCC8	Scaffold/PPI	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, WD40_repeat_CS

Expression context

Cohort genes with no expression data: 0.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adrenal tissue	1
primordial germ cell in gonad	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ERCC8	218	ubiquitous	yes	adrenal tissue, ventricular zone, primordial germ cell in gonad

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ERCC8	1,550

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ERCC8	Q13216	16

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Transcription-Coupled Nucleotide Excision Repair (TC-NER)	1	265.6×	0.007	ERCC8
Formation of TC-NER Pre-Incision Complex	1	211.5×	0.007	ERCC8
Gap-filling DNA repair synthesis and ligation in TC-NER	1	178.4×	0.007	ERCC8
Dual incision in TC-NER	1	173.0×	0.007	ERCC8
Neddylation	1	47.4×	0.021	ERCC8

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of transcription-coupled nucleotide-excision repair	1	16852.0×	8e-04	ERCC8
double-strand break repair via classical nonhomologous end joining	1	1685.2×	0.003	ERCC8
single strand break repair	1	1404.3×	0.003	ERCC8
transcription-coupled nucleotide-excision repair	1	1203.7×	0.003	ERCC8
response to X-ray	1	887.0×	0.003	ERCC8
response to auditory stimulus	1	732.7×	0.003	ERCC8
response to UV	1	366.4×	0.005	ERCC8
positive regulation of DNA repair	1	358.6×	0.005	ERCC8
protein autoubiquitination	1	234.1×	0.007	ERCC8
response to oxidative stress	1	130.6×	0.011	ERCC8
protein polyubiquitination	1	115.4×	0.011	ERCC8
DNA damage response	1	53.5×	0.021	ERCC8
proteasome-mediated ubiquitin-dependent protein catabolic process	1	52.2×	0.021	ERCC8
protein ubiquitination	1	41.4×	0.024	ERCC8

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ERCC8	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	ERCC8

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
ERCC8	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.