Xeroderma pigmentosum variant type

Summary

Xeroderma pigmentosum variant type (MONDO:0010214) is a disease caused by POLH (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: POLH (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 246
• Phenotypes (HPO): 13

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		50	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

13 HPO clinical features (Orphanet curated; top 13 by frequency):

HPO ID	Term	Frequency
HP:0000953	Hyperpigmentation of the skin	Very frequent (80-99%)
HP:0000992	Cutaneous photosensitivity	Very frequent (80-99%)
HP:0001010	Hypopigmentation of the skin	Very frequent (80-99%)
HP:0001029	Poikiloderma	Very frequent (80-99%)
HP:0007603	Freckles in sun-exposed areas	Very frequent (80-99%)
HP:0000491	Keratitis	Frequent (30-79%)
HP:0000613	Photophobia	Frequent (30-79%)
HP:0000958	Dry skin	Frequent (30-79%)
HP:0001009	Telangiectasia	Frequent (30-79%)
HP:0002671	Basal cell carcinoma	Frequent (30-79%)
HP:0002860	Squamous cell carcinoma	Frequent (30-79%)
HP:0002861	Melanoma	Frequent (30-79%)
HP:0004334	Dermal atrophy	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	xeroderma pigmentosum variant type
Mondo ID	MONDO:0010214
MeSH	C536766
OMIM	278750
Orphanet	90342
DOID	DOID:0110847
NCIT	C141367
UMLS	C1848410
MedGen	376352
GARD	0005630
Is cancer (heuristic)	no

Also known as: photosensitivity with defective DNA synthesis · xeroderma pigmentosum variant type · xeroderma pigmentosum with normal DNA repair rates · xeroderma pigmentosum, variant type · XPV

Data availability: 246 ClinVar variants · 6 GenCC gene-disease records · 127 cell lines.

Disease family

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

Related subtypes (9): xeroderma pigmentosum, autosomal dominant, mild, xeroderma pigmentosum group A, xeroderma pigmentosum group C, xeroderma pigmentosum group D, xeroderma pigmentosum group E, 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

246 retrieved; paginated sample, class counts are floors:

142 uncertain significance, 36 benign, 18 conflicting classifications of pathogenicity, 17 pathogenic, 12 likely benign, 8 likely pathogenic, 7 benign/likely benign, 5 pathogenic/likely pathogenic, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1119983	NM_006502.3(POLH):c.672_673insT (p.Leu225fs)	POLH	Pathogenic	criteria provided, multiple submitters, no conflicts
1459259	NM_006502.3(POLH):c.1066C>T (p.Arg356Ter)	POLH	Pathogenic	criteria provided, multiple submitters, no conflicts
1686085	NM_006502.3(POLH):c.638C>G (p.Ser213Ter)	POLH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
224062	NM_006502.3(POLH):c.764+1G>A	POLH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
224063	NM_006502.3(POLH):c.907C>T (p.Arg303Ter)	POLH	Pathogenic	criteria provided, multiple submitters, no conflicts
225444	NM_006502.3(POLH):c.490G>T (p.Glu164Ter)	POLH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2431387	NM_006502.3(POLH):c.1222_1225del (p.Thr408fs)	POLH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
264680	NM_006502.3(POLH):c.725C>G (p.Ser242Ter)	POLH	Pathogenic	criteria provided, single submitter
264682	NM_006502.2(POLH):c.1075-?_1244+?del	POLH	Pathogenic	no assertion criteria provided
2734868	NM_006502.3(POLH):c.499C>T (p.Arg167Ter)	POLH	Pathogenic	criteria provided, multiple submitters, no conflicts
4292256	NM_006502.3(POLH):c.505C>T (p.Gln169Ter)	POLH	Pathogenic	criteria provided, single submitter
5884	NM_006502.3(POLH):c.106_118del (p.Val36fs)	POLH	Pathogenic	criteria provided, single submitter
5885	NM_006502.3(POLH):c.54_57del (p.Val19fs)	POLH	Pathogenic	no assertion criteria provided
5886	POLH, 2-BP DEL, NT770	POLH	Pathogenic	no assertion criteria provided
5887	NM_006502.3(POLH):c.916G>T (p.Glu306Ter)	POLH	Pathogenic	no assertion criteria provided
5888	POLH, DEL AND TRP297TER	POLH	Pathogenic	no assertion criteria provided
5889	NM_006502.3(POLH):c.376C>T (p.Gln126Ter)	POLH	Pathogenic	criteria provided, single submitter
5890	NM_006502.3(POLH):c.1117C>T (p.Gln373Ter)	POLH	Pathogenic	criteria provided, single submitter
5891	NM_006502.3(POLH):c.663_764+2del	POLH	Pathogenic	no assertion criteria provided
5892	NM_006502.3(POLH):c.207del (p.Lys70fs)	POLH	Pathogenic	criteria provided, single submitter
5893	NM_006502.3(POLH):c.222TCT[1] (p.Leu77del)	POLH	Pathogenic	no assertion criteria provided
631984	NM_006502.3(POLH):c.149dup (p.Ser51fs)	POLH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1333587	NM_006502.3(POLH):c.1561C>T (p.Gln521Ter)	POLH	Likely pathogenic	criteria provided, single submitter
2682158	NM_006502.3(POLH):c.571A>C (p.Thr191Pro)	POLH	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3593646	NM_006502.3(POLH):c.19C>T (p.Arg7Ter)	POLH	Likely pathogenic	criteria provided, single submitter
3593647	NM_006502.3(POLH):c.53_54del (p.Phe18fs)	POLH	Likely pathogenic	criteria provided, single submitter
3593649	NM_006502.3(POLH):c.533_534del (p.Leu178fs)	POLH	Likely pathogenic	criteria provided, single submitter
3593650	NM_006502.3(POLH):c.788G>T (p.Gly263Val)	POLH	Likely pathogenic	criteria provided, single submitter
3593654	NM_006502.3(POLH):c.1727_1728del (p.Pro576fs)	POLH	Likely pathogenic	criteria provided, single submitter
3593655	NM_006502.3(POLH):c.2130dup (p.Leu711fs)	POLH	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 1 · 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
POLH	Definitive	Autosomal recessive	xeroderma pigmentosum variant type	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
POLH	Orphanet:90342	Xeroderma pigmentosum variant

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
POLH	HGNC:9181	ENSG00000170734	Q9Y253	DNA polymerase eta	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
POLH	DNA polymerase eta	DNA polymerase specifically involved in the DNA repair by translesion synthesis (TLS).

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
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.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	1
skeletal muscle tissue of rectus abdominis	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
POLH	283	ubiquitous	marker	buccal mucosa cell, skeletal muscle tissue of rectus abdominis, stromal cell of endometrium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
POLH	1,789

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
POLH	Q9Y253	241

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
Translesion Synthesis by POLH	1	601.0×	0.004	POLH
Termination of translesion DNA synthesis	1	346.1×	0.004	POLH
HDR through Homologous Recombination (HRR)	1	190.3×	0.005	POLH

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
pyrimidine dimer repair	1	4213.0×	1e-03	POLH
error-free translesion synthesis	1	3370.4×	1e-03	POLH
cellular response to UV-C	1	3370.4×	1e-03	POLH
response to UV-C	1	1685.2×	0.001	POLH
error-prone translesion synthesis	1	1532.0×	0.001	POLH
response to radiation	1	1203.7×	0.001	POLH
DNA synthesis involved in DNA repair	1	936.2×	0.002	POLH
regulation of DNA repair	1	276.3×	0.005	POLH
DNA replication	1	165.2×	0.007	POLH
DNA repair	1	63.8×	0.016	POLH

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) 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
POLH	CANDESARTAN CILEXETIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
POLH	7	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CANDESARTAN CILEXETIL	4	POLH
QUERCETIN	3	POLH
LUTEOLIN	2	POLH
GENISTEIN	2	POLH
ELLAGIC ACID	2	POLH
BAICALEIN	2	POLH
KAEMPFEROL	1	POLH

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
POLH	18	Binding:16, Functional:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
POLH	2.7.7.7	DNA-directed DNA polymerase

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

7 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)
CANDESARTAN CILEXETIL	4	POLH
QUERCETIN	3	POLH
LUTEOLIN	2	POLH
GENISTEIN	2	POLH
ELLAGIC ACID	2	POLH
BAICALEIN	2	POLH
KAEMPFEROL	1	POLH

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.