Xeroderma pigmentosum

disease

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Also known as angioma pigmentosum atrophicumatrophoderma pigmentosumKaposi dermatosisKaposi diseasemelanosis lenticularis progressivapigmented epitheliomatosisxeroderma of Kaposixeroderma pigmentosaxeroderma pigmentosum syndromeXP

Summary

Xeroderma pigmentosum (MONDO:0019600) is a disease (an umbrella term covering 10 Mondo subtypes) with 9 cohort genes and 10 clinical trials. The dominant Reactome pathway is Formation of Incision Complex in GG-NER (7 cohort genes). Top therapeutic interventions include afamelanotide and ipilimumab.

At a glance

Prevalence: 1-9 / 1 000 000 (United States) [Orphanet-validated]
Umbrella term: 10 Mondo subtypes
Cohort genes: 9
ClinVar variants: 394
Phenotypes (HPO): 59
Clinical trials: 10

Clinical features

Epidemiology

Prevalence records

9 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000	0.1	United States	Validated
Point prevalence	1-9 / 100 000	4.5	Japan	Validated
Prevalence at birth	1-9 / 1 000 000	0.19	United Kingdom	Validated
Prevalence at birth	1-9 / 1 000 000	0.41	Netherlands	Validated
Prevalence at birth	1-9 / 1 000 000	0.16	Italy	Validated
Prevalence at birth	1-9 / 1 000 000	0.34	France	Validated
Prevalence at birth	1-9 / 1 000 000	0.18	Germany	Validated
Prevalence at birth	1-9 / 1 000 000	0.23	Europe	Not yet validated
Annual incidence	1-9 / 100 000	1.75	Libyan Arab Jamahiriya	Not yet validated

Signs & symptoms

Clinical features (HPO)

59 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000135	Hypogonadism	Very frequent (80-99%)
HP:0000164	Abnormality of the dentition	Very frequent (80-99%)
HP:0000524	Conjunctival telangiectasia	Very frequent (80-99%)
HP:0000648	Optic atrophy	Very frequent (80-99%)
HP:0000958	Dry skin	Very frequent (80-99%)
HP:0000963	Thin skin	Very frequent (80-99%)
HP:0000992	Cutaneous photosensitivity	Very frequent (80-99%)
HP:0001009	Telangiectasia	Very frequent (80-99%)
HP:0001029	Poikiloderma	Very frequent (80-99%)
HP:0001072	Thickened skin	Very frequent (80-99%)
HP:0001480	Freckling	Very frequent (80-99%)
HP:0001508	Failure to thrive	Very frequent (80-99%)
HP:0001945	Fever	Very frequent (80-99%)
HP:0002353	EEG abnormality	Very frequent (80-99%)
HP:0002376	Developmental regression	Very frequent (80-99%)
HP:0002829	Arthralgia	Very frequent (80-99%)
HP:0006887	Intellectual disability, progressive	Very frequent (80-99%)
HP:0012378	Fatigue	Very frequent (80-99%)
HP:0100543	Cognitive impairment	Very frequent (80-99%)
HP:0100585	Telangiectasia of the skin	Very frequent (80-99%)
HP:0000028	Cryptorchidism	Frequent (30-79%)
HP:0000407	Sensorineural hearing impairment	Frequent (30-79%)
HP:0000486	Strabismus	Frequent (30-79%)
HP:0000491	Keratitis	Frequent (30-79%)
HP:0000518	Cataract	Frequent (30-79%)
HP:0000962	Hyperkeratosis	Frequent (30-79%)
HP:0001034	Hypermelanotic macule	Frequent (30-79%)
HP:0001053	Hypopigmented skin patches	Frequent (30-79%)
HP:0002861	Melanoma	Frequent (30-79%)
HP:0004334	Dermal atrophy	Frequent (30-79%)
HP:0010783	Erythema	Frequent (30-79%)
HP:0012733	Macule	Frequent (30-79%)
HP:0012740	Papilloma	Frequent (30-79%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0000365	Hearing impairment	Occasional (5-29%)
HP:0000498	Blepharitis	Occasional (5-29%)
HP:0000613	Photophobia	Occasional (5-29%)
HP:0000621	Entropion	Occasional (5-29%)
HP:0000656	Ectropion	Occasional (5-29%)
HP:0000995	Melanocytic nevus	Occasional (5-29%)
HP:0001059	Pterygium	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001257	Spasticity	Occasional (5-29%)
HP:0001315	Reduced tendon reflexes	Occasional (5-29%)
HP:0001596	Alopecia	Occasional (5-29%)
HP:0002071	Abnormality of extrapyramidal motor function	Occasional (5-29%)
HP:0002120	Cerebral cortical atrophy	Occasional (5-29%)
HP:0002664	Neoplasm	Occasional (5-29%)
HP:0002750	Delayed skeletal maturation	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	xeroderma pigmentosum
Mondo ID	MONDO:0019600
MeSH	D014983
OMIM	278700
Orphanet	910
DOID	DOID:0050427
ICD-10-CM	Q82.1
ICD-11	1243068849
NCIT	C3452
SNOMED CT	44600005
UMLS	C0043346
MedGen	21943
GARD	0007910
MedDRA	10048220
NORD	1870
Is cancer (heuristic)	no

Also known as: angioma pigmentosum atrophicum · atrophoderma pigmentosum · Kaposi dermatosis · Kaposi disease · melanosis lenticularis progressiva · pigmented epitheliomatosis · xeroderma of Kaposi · xeroderma pigmentosa · xeroderma pigmentosum syndrome · XP

Data availability: 394 ClinVar variants · 7 GenCC gene-disease records · 691 cell lines.

Disease family

An umbrella term covering 10 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary skin disorder › hereditary photodermatosis › xeroderma pigmentosum

Subtypes (10): xeroderma pigmentosum, autosomal dominant, mild, xeroderma pigmentosum group A, xeroderma pigmentosum group C, xeroderma pigmentosum group D, xeroderma pigmentosum group E, xeroderma pigmentosum variant type, xeroderma pigmentosum group F, xeroderma pigmentosum group G, xeroderma pigmentosum group B, xeroderma pigmentosum, complementation group J

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

394 retrieved; paginated sample, class counts are floors:

114 uncertain significance, 93 conflicting classifications of pathogenicity, 54 likely benign, 43 pathogenic, 35 pathogenic/likely pathogenic, 29 benign/likely benign, 26 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2429148	NM_000400.4(ERCC2):c.[1381C>G;2150C>G]		Pathogenic	criteria provided, single submitter
1065165	NM_000123.4(ERCC5):c.2606_2607del (p.Val869fs)	BIVM-ERCC5	Pathogenic	criteria provided, multiple submitters, no conflicts
16566	NM_000123.4(ERCC5):c.2878G>T (p.Glu960Ter)	BIVM-ERCC5	Pathogenic	criteria provided, multiple submitters, no conflicts
16576	NM_000123.4(ERCC5):c.2751del (p.Lys917fs)	BIVM-ERCC5	Pathogenic	criteria provided, multiple submitters, no conflicts
1696064	NM_000123.4(ERCC5):c.1975del (p.Ser659fs)	BIVM-ERCC5	Pathogenic	criteria provided, single submitter
3064167	NM_000123.4(ERCC5):c.205C>T (p.Arg69Ter)	BIVM-ERCC5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
517221	NM_000123.4(ERCC5):c.1173dup (p.Lys392Ter)	BIVM-ERCC5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
800881	NM_000123.4(ERCC5):c.2427del (p.Asp809fs)	BIVM-ERCC5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
929130	NM_000123.4(ERCC5):c.922_923del (p.Leu308fs)	BIVM-ERCC5	Pathogenic	criteria provided, single submitter
932539	NM_000123.4(ERCC5):c.2413G>A (p.Gly805Arg)	BIVM-ERCC5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
996657	NM_000123.4(ERCC5):c.2453C>T (p.Ala818Val)	BIVM-ERCC5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3366825	NC_000011.9:g.(47238024_47238408)_(47254511_47256123)del	DDB2	Pathogenic	criteria provided, single submitter
134095	NM_000400.4(ERCC2):c.1703_1704del (p.Phe568fs)	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
134102	NM_000400.4(ERCC2):c.2150C>G (p.Ala717Gly)	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1511660	NM_000400.4(ERCC2):c.2190+1del	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16781	NM_000400.4(ERCC2):c.2173G>C (p.Ala725Pro)	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16783	NM_000400.4(ERCC2):c.1621A>C (p.Ser541Arg)	ERCC2	Pathogenic	criteria provided, single submitter
16788	NM_000400.4(ERCC2):c.1846C>T (p.Arg616Trp)	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1705082	NM_000400.4(ERCC2):c.2141_2148del (p.Val714fs)	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1705248	NM_000400.4(ERCC2):c.195_196delinsTT (p.Glu66Ter)	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2506192	NM_000400.4(ERCC2):c.262C>T (p.Arg88Ter)	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2573404	NM_000400.4(ERCC2):c.1802G>T (p.Arg601Leu)	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2675051	NM_000400.4(ERCC2):c.1852_1871dup (p.Tyr625fs)	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3241411	NM_000400.4(ERCC2):c.1532G>A (p.Arg511Gln)	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
329508	NM_000400.4(ERCC2):c.1847G>C (p.Arg616Pro)	ERCC2	Pathogenic	criteria provided, multiple submitters, no conflicts
329511	NM_000400.4(ERCC2):c.1479+2dup	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
329522	NM_000400.4(ERCC2):c.776G>A (p.Cys259Tyr)	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
402226	NM_000400.4(ERCC2):c.594+2_594+5del	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
445466	NM_000400.4(ERCC2):c.2005del (p.Arg669fs)	ERCC2	Pathogenic	criteria provided, multiple submitters, no conflicts
620626	NM_000400.4(ERCC2):c.1361TCA[2] (p.Ile456del)	ERCC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 73 · Orphanet: 18 · 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
DDB2	Definitive	Autosomal recessive	xeroderma pigmentosum group E	6
ERCC2	Definitive	Autosomal recessive	xeroderma pigmentosum group D	19
ERCC3	Definitive	Autosomal recessive	xeroderma pigmentosum group B	12
ERCC4	Definitive	Autosomal recessive	xeroderma pigmentosum group F	11
ERCC5	Definitive	Autosomal recessive	xeroderma pigmentosum group G	11
XPA	Definitive	Autosomal recessive	xeroderma pigmentosum group A	7
XPC	Definitive	Autosomal recessive	xeroderma pigmentosum group C	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
XPA	Orphanet:910	Xeroderma pigmentosum
XPC	Orphanet:910	Xeroderma pigmentosum
DDB2	Orphanet:910	Xeroderma pigmentosum
ERCC2	Orphanet:1466	COFS syndrome
ERCC2	Orphanet:220295	Xeroderma pigmentosum-Cockayne syndrome complex
ERCC2	Orphanet:33364	Trichothiodystrophy
ERCC2	Orphanet:910	Xeroderma pigmentosum
ERCC3	Orphanet:220295	Xeroderma pigmentosum-Cockayne syndrome complex
ERCC3	Orphanet:33364	Trichothiodystrophy
ERCC3	Orphanet:910	Xeroderma pigmentosum
ERCC4	Orphanet:220295	Xeroderma pigmentosum-Cockayne syndrome complex
ERCC4	Orphanet:84	Fanconi anemia
ERCC4	Orphanet:90321	Cockayne syndrome type 1
ERCC4	Orphanet:910	Xeroderma pigmentosum
ERCC5	Orphanet:1466	COFS syndrome
ERCC5	Orphanet:220295	Xeroderma pigmentosum-Cockayne syndrome complex
ERCC5	Orphanet:910	Xeroderma pigmentosum
POLH	Orphanet:90342	Xeroderma pigmentosum variant

Cohort genes → proteins

9 cohort genes, 8 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	9

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
XPA	HGNC:12814	ENSG00000136936	P23025	DNA repair protein complementing XP-A cells	gencc,clinvar
XPC	HGNC:12816	ENSG00000154767	Q01831	DNA repair protein complementing XP-C cells	gencc,clinvar
DDB2	HGNC:2718	ENSG00000134574	Q92466	DNA damage-binding protein 2	gencc,clinvar
ERCC2	HGNC:3434	ENSG00000104884	P18074	General transcription and DNA repair factor IIH helicase subunit XPD	gencc,clinvar
ERCC3	HGNC:3435	ENSG00000163161	P19447	General transcription and DNA repair factor IIH helicase/translocase subunit XPB	gencc,clinvar
ERCC4	HGNC:3436	ENSG00000175595	Q92889	DNA repair endonuclease XPF	gencc,clinvar
ERCC5	HGNC:3437	ENSG00000134899	P28715	DNA excision repair protein ERCC-5	gencc
BIVM-ERCC5	HGNC:43690	ENSG00000270181		BIVM-ERCC5 readthrough	clinvar
POLH	HGNC:9181	ENSG00000170734	Q9Y253	DNA polymerase eta	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
XPA	DNA repair protein complementing XP-A cells	Involved in DNA nucleotide excision repair (NER).
XPC	DNA repair protein complementing XP-C cells	Involved in global genome nucleotide excision repair (GG-NER) by acting as damage sensing and DNA-binding factor component of the XPC complex.
DDB2	DNA damage-binding protein 2	Protein, which is both involved in DNA repair and protein ubiquitination, as part of the UV-DDB complex and DCX (DDB1-CUL4-X-box) complexes, respectively.
ERCC2	General transcription and DNA repair factor IIH helicase subunit XPD	ATP-dependent 5’-3’ DNA helicase.
ERCC3	General transcription and DNA repair factor IIH helicase/translocase subunit XPB	ATP-dependent 3’-5’ DNA helicase/translocase.
ERCC4	DNA repair endonuclease XPF	Catalytic component of a structure-specific DNA repair endonuclease responsible for the 5-prime incision during DNA repair, and which is essential for nucleotide excision repair (NER) and interstrand cross-link (ICL) repair.
ERCC5	DNA excision repair protein ERCC-5	Single-stranded structure-specific DNA endonuclease involved in DNA excision repair.
POLH	DNA polymerase eta	DNA polymerase specifically involved in the DNA repair by translesion synthesis (TLS).

Protein-family classification

Druggable: 2 · Difficult: 2 · Unknown: 5 · Druggable fraction: 0.22

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
Enzyme (other)	2	2.7×	0.677
Scaffold/PPI	1	1.9×	0.687
Other/Unknown	5	1.0×	0.687
Transcription factor	1	0.9×	0.687

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
XPA	Transcription factor	no		XPA/RAD14, DNA-bd_dom_put_sf, Znf_XPA_CS
XPC	Other/Unknown	no		DNA_repair_Rad4, DNA_repair_Rad4-like, Rad4/PNGase_transGLS-fold
DDB2	Scaffold/PPI	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, WD40_repeat_CS
ERCC2	Enzyme (other)	yes	3.6.4.12	RAD3/XPD, DNA/RNA_helicase_DEAH_CS, Helicase-like_DEXD_c2
ERCC3	Other/Unknown	no		XPB/Ssl2, Helicase_C-like, Helicase/UvrB_N
ERCC4	Other/Unknown	no		ERCC4_domain, XPF, RuvA_2-like
ERCC5	Other/Unknown	no		XPG/Rad2_eukaryotes, XPG/Rad2, XPG_DNA_repair_N
BIVM-ERCC5	Other/Unknown	no
POLH	Enzyme (other)	yes	2.7.7.7	UmuC, DNA_pol_Y-fam_little_finger, DNA_pol_Y-fam_lit_finger_sf

Expression context

Cohort genes with no expression data: 0.

7 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	9
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	3
sural nerve	2
stromal cell of endometrium	2
male germ line stem cell (sensu Vertebrata) in testis	2
Brodmann (1909) area 23	1
left lobe of thyroid gland	1
mucosa of stomach	1
right uterine tube	1
skin of abdomen	1
skin of leg	1
left adrenal gland	1
right adrenal gland	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
adrenal tissue	1
sperm	1
body of pancreas	1
granulocyte	1
tonsil	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
XPA	289	ubiquitous	marker	calcaneal tendon, Brodmann (1909) area 23, left lobe of thyroid gland
XPC	295	ubiquitous	marker	sural nerve, calcaneal tendon, mucosa of stomach
DDB2	235	ubiquitous	marker	skin of abdomen, skin of leg, right uterine tube
ERCC2	184	ubiquitous	marker	stromal cell of endometrium, right adrenal gland, left adrenal gland
ERCC3	277	ubiquitous	marker	sural nerve, right hemisphere of cerebellum, cerebellar hemisphere
ERCC4	242	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, adrenal tissue, sperm
ERCC5	166	ubiquitous	yes	granulocyte, calcaneal tendon, body of pancreas
BIVM-ERCC5	108	ubiquitous	yes	male germ line stem cell (sensu Vertebrata) in testis, tonsil, ventricular zone
POLH	283	ubiquitous	marker	buccal mucosa cell, skeletal muscle tissue of rectus abdominis, stromal cell of endometrium

Protein interactions among cohort

Intra-cohort edges: 18.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ERCC3	3,219
ERCC5	2,749
ERCC2	2,746
DDB2	2,628
ERCC4	2,102
XPA	1,988
XPC	1,916
POLH	1,789
BIVM-ERCC5	0

Intra-cohort edges

A	B	Sources
DDB2	ERCC2	string_interaction
DDB2	ERCC3	string_interaction
DDB2	XPA	string_interaction
DDB2	XPC	string_interaction
ERCC2	ERCC3	intact, string_interaction
ERCC2	ERCC4	string_interaction
ERCC2	ERCC5	string_interaction
ERCC2	XPA	biogrid_interaction, string_interaction
ERCC2	XPC	string_interaction
ERCC3	ERCC4	string_interaction
ERCC3	ERCC5	intact, string_interaction
ERCC3	XPA	string_interaction
ERCC3	XPC	intact, string_interaction
ERCC4	ERCC5	string_interaction
ERCC4	XPA	biogrid_interaction, intact, string_interaction
ERCC4	XPC	string_interaction
ERCC5	XPA	string_interaction
XPA	XPC	string_interaction

Structural data

PDB: 8 · AlphaFold-only: 0 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
POLH	Q9Y253	241
ERCC3	P19447	52
ERCC2	P18074	51
XPA	P23025	18
XPC	Q01831	18
ERCC4	Q92889	13
DDB2	Q92466	10
ERCC5	P28715	10

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 39. Enrichment computed across 9 evidence-associated genes (8 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 8 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Formation of Incision Complex in GG-NER	7	222.1×	3e-15	XPA, XPC, DDB2, ERCC2, ERCC3, ERCC4, ERCC5
Dual Incision in GG-NER	6	194.7×	1e-12	XPA, DDB2, ERCC2, ERCC3, ERCC4, ERCC5
Dual incision in TC-NER	5	108.1×	4e-09	XPA, ERCC2, ERCC3, ERCC4, ERCC5
Formation of TC-NER Pre-Incision Complex	3	79.3×	5e-05	XPA, ERCC2, ERCC3
TP53 Regulates Transcription of DNA Repair Genes	3	68.0×	7e-05	DDB2, ERCC2, ERCC3
RNA Pol II CTD phosphorylation and interaction with CE during HIV infection	2	102.0×	9e-04	ERCC2, ERCC3
RNA Pol II CTD phosphorylation and interaction with CE	2	102.0×	9e-04	ERCC2, ERCC3
mRNA Capping	2	95.2×	9e-04	ERCC2, ERCC3
Formation of the Early Elongation Complex	2	84.0×	9e-04	ERCC2, ERCC3
Formation of the HIV-1 Early Elongation Complex	2	84.0×	9e-04	ERCC2, ERCC3
RNA Polymerase I Transcription Termination	2	81.6×	9e-04	ERCC2, ERCC3
DNA Damage Recognition in GG-NER	2	71.4×	9e-04	XPC, DDB2
Transcription-Coupled Nucleotide Excision Repair (TC-NER)	2	66.4×	9e-04	ERCC2, ERCC3
Formation of HIV-1 elongation complex containing HIV-1 Tat	2	64.9×	9e-04	ERCC2, ERCC3
Tat-mediated elongation of the HIV-1 transcript	2	64.9×	9e-04	ERCC2, ERCC3
Formation of HIV elongation complex in the absence of HIV Tat	2	62.1×	9e-04	ERCC2, ERCC3
HIV Transcription Initiation	2	58.3×	9e-04	ERCC2, ERCC3
RNA Polymerase II HIV Promoter Escape	2	58.3×	9e-04	ERCC2, ERCC3
RNA Polymerase II Promoter Escape	2	58.3×	9e-04	ERCC2, ERCC3
RNA Polymerase II Transcription Pre-Initiation And Promoter Opening	2	58.3×	9e-04	ERCC2, ERCC3
RNA Polymerase II Transcription Initiation	2	58.3×	9e-04	ERCC2, ERCC3
RNA Polymerase II Transcription Initiation And Promoter Clearance	2	58.3×	9e-04	ERCC2, ERCC3
RNA Polymerase I Transcription Initiation	2	56.0×	9e-04	ERCC2, ERCC3
Formation of RNA Pol II elongation complex	2	48.4×	0.001	ERCC2, ERCC3
RNA Polymerase II Transcription Elongation	2	48.4×	0.001	ERCC2, ERCC3
Gap-filling DNA repair synthesis and ligation in TC-NER	2	44.6×	0.001	ERCC2, ERCC3
Transcription of the HIV genome	2	43.3×	0.001	ERCC2, ERCC3
RNA Polymerase II Pre-transcription Events	2	34.4×	0.002	ERCC2, ERCC3
RNA Polymerase I Promoter Escape	2	30.4×	0.002	ERCC2, ERCC3
NoRC negatively regulates rRNA expression	2	26.2×	0.003	ERCC2, ERCC3

GO biological processes by enrichment

GO term	Cohort genes	Fold	FDR	Sample cohort genes
nucleotide-excision repair	7	335.1×	3e-16	XPA, XPC, DDB2, ERCC2, ERCC3, ERCC4, ERCC5
UV protection	4	601.9×	8e-10	XPA, ERCC2, ERCC3, ERCC4
DNA repair	6	47.9×	1e-08	XPA, XPC, DDB2, ERCC3, ERCC4, POLH
response to UV	4	183.2×	6e-08	DDB2, ERCC3, ERCC4, ERCC5
regulation of mitotic cell cycle phase transition	3	632.0×	1e-07	XPC, ERCC2, ERCC3
UV-damage excision repair	3	486.1×	3e-07	XPA, XPC, DDB2
transcription-coupled nucleotide-excision repair	3	451.4×	3e-07	ERCC2, ERCC3, ERCC5
nucleotide-excision repair involved in interstrand cross-link repair	2	1404.3×	6e-06	XPA, ERCC4
pyrimidine dimer repair	2	1053.2×	1e-05	DDB2, POLH
hair cell differentiation	2	526.6×	4e-05	ERCC2, ERCC3
response to UV-C	2	421.3×	6e-05	ERCC5, POLH
response to oxidative stress	3	49.0×	2e-04	XPA, ERCC2, ERCC3
embryonic organ development	2	120.4×	7e-04	ERCC2, ERCC3
transcription initiation at RNA polymerase II promoter	2	93.6×	0.001	ERCC2, ERCC3
cellular response to UV	2	73.9×	0.002	DDB2, ERCC4
nucleotide-excision repair, DNA damage recognition	1	2106.5×	0.002	XPA
regulation of autophagy	2	60.2×	0.002	XPA, ERCC4
positive regulation of mitotic recombination	1	1053.2×	0.004	ERCC2
double-strand break repair via homologous recombination	2	39.0×	0.004	ERCC4, ERCC5
multicellular organism growth	2	34.2×	0.005	XPA, ERCC2
pyrimidine dimer repair by nucleotide-excision repair	1	526.6×	0.006	XPC
telomeric DNA-containing double minutes formation	1	526.6×	0.006	ERCC4
negative regulation of protection from non-homologous end joining at telomere	1	526.6×	0.006	ERCC4
base-excision repair, AP site formation	1	421.3×	0.007	ERCC5
error-free translesion synthesis	1	421.3×	0.007	POLH
cellular response to UV-C	1	421.3×	0.007	POLH
negative regulation of telomere maintenance	1	351.1×	0.008	ERCC4
central nervous system myelin formation	1	300.9×	0.009	ERCC2
transcription elongation by RNA polymerase I	1	263.3×	0.010	ERCC2
hair follicle maturation	1	263.3×	0.010	ERCC2

Therapeutics

Drugs indicated or in trials for this disease

No drug has an approved disease-direct ChEMBL indication for this disease.

1 drug in clinical trials for this disease (phase 2–3, investigational): efficacy not established — a trial record, not an indication.

Drug	Highest phase
Afamelanotide	Phase 2

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 7

Druggability breadth: 6 of 9 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
ERCC2	SUNITINIB
POLH	CANDESARTAN CILEXETIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ERCC2	16	4
POLH	7	4
XPA	0	0
XPC	0	0
DDB2	0	0
ERCC3	0	0
ERCC4	0	0
ERCC5	0	0
BIVM-ERCC5	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SUNITINIB	4	ERCC2
CANDESARTAN CILEXETIL	4	POLH
DINACICLIB	3	ERCC2
DEFACTINIB	3	ERCC2
ALVOCIDIB	3	ERCC2
QUERCETIN	3	POLH
SELICICLIB	2	ERCC2
ZOTIRACICLIB	2	ERCC2
DANUSERTIB	2	ERCC2
MILCICLIB	2	ERCC2
LUTEOLIN	2	POLH
GENISTEIN	2	POLH
ELLAGIC ACID	2	POLH
BAICALEIN	2	POLH
PF-00562271	1	ERCC2
PHA-793887	1	ERCC2
KW-2449	1	ERCC2
BMS-387032	1	ERCC2
PF-03758309	1	ERCC2
TAK-901	1	ERCC2
RGB-286638	1	ERCC2
XL-228	1	ERCC2
KAEMPFEROL	1	POLH

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
ERCC4	28	Binding:28
POLH	18	Binding:16, Functional:2
XPA	6	Binding:6
ERCC2	3	Binding:3
ERCC5	3	Binding:3
ERCC3	1	ADMET:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ERCC2	3.6.4.12	DNA helicase
POLH	2.7.7.7	DNA-directed DNA polymerase

Pharmacogenomics

Cohort genes with a PharmGKB record: 8; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

23 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.

Compound	Max phase	Cohort target (bioactivity)
SUNITINIB	4	ERCC2
CANDESARTAN CILEXETIL	4	POLH
DINACICLIB	3	ERCC2
DEFACTINIB	3	ERCC2
ALVOCIDIB	3	ERCC2
QUERCETIN	3	POLH
SELICICLIB	2	ERCC2
ZOTIRACICLIB	2	ERCC2
DANUSERTIB	2	ERCC2
MILCICLIB	2	ERCC2
LUTEOLIN	2	POLH
GENISTEIN	2	POLH
ELLAGIC ACID	2	POLH
BAICALEIN	2	POLH
PF-00562271	1	ERCC2
PHA-793887	1	ERCC2
KW-2449	1	ERCC2
BMS-387032	1	ERCC2
PF-03758309	1	ERCC2
TAK-901	1	ERCC2
RGB-286638	1	ERCC2
XL-228	1	ERCC2
KAEMPFEROL	1	POLH

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	ERCC2, POLH
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	7	XPA, XPC, DDB2, ERCC3, ERCC4, ERCC5, BIVM-ERCC5

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
XPA	6	ERCC2
ERCC3	1	ERCC2
ERCC4	28	ERCC2
ERCC5	3	ERCC2
XPC	0	—
DDB2	0	—
BIVM-ERCC5	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 10.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	7
PHASE2	2
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05159752	PHASE2	UNKNOWN	A Study to Evaluate the Safety and Efficacy of Afamelanotide in Patients With Xeroderma Pigmentosum (XP)
NCT05370235	PHASE2	UNKNOWN	A Study to Evaluate the Safety and Efficacy of Afamelanotide in Patients With Xeroderma Pigmentosum C and V
NCT04500548	PHASE1	WITHDRAWN	Testing the Combination of Two Immunotherapy Drugs (Nivolumab and Ipilimumab) in Children, Adolescent, and Young Adult Patients With Relapsed/Refractory Cancers That Have an Increased Number of Genetic Changes, The 3CI Study
NCT05484570	Not specified	RECRUITING	Natural History Study for DNA Repair Disorders
NCT06330324	Not specified	ENROLLING_BY_INVITATION	Reproductive Options in Inherited Skin Diseases
NCT00001813	Not specified	COMPLETED	Examination of Clinical and Laboratory Abnormalities in Patients With Defective DNA Repair: Xeroderma Pigmentosum, Cockayne Syndrome, or Trichothiodystrophy
NCT00046189	Not specified	COMPLETED	Cancer Risk in Carriers of the Gene for Xeroderma Pigmentosum
NCT00555633	Not specified	COMPLETED	Use of an SPF30 Sunscreen and an After-sun-lotion in Skin Cancer Risk Patients
NCT01123694	Not specified	UNKNOWN	Xeroderma Pigmentosum Patient Experiences
NCT03445052	Not specified	COMPLETED	XPAND Trial: Enhancing XP Photoprotection Activities - New Directions

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
AFAMELANOTIDE	4	2
IPILIMUMAB	4	1

Cohort genes: XPA, XPC, DDB2, ERCC2, ERCC3, ERCC4, ERCC5, POLH
Drugs: Afamelanotide, Ipilimumab