xeroderma pigmentosum group A

Summary

xeroderma pigmentosum group A (MONDO:0010210) is a disease caused by XPA (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: XPA (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 147

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	xeroderma pigmentosum group A
Mondo ID	MONDO:0010210
OMIM	278700
Orphanet	276249
DOID	DOID:0110843
NCIT	C3965
SNOMED CT	43477006
UMLS	C0268135
MedGen	82775
GARD	0005624
Is cancer (heuristic)	no

Also known as: xeroderma pigmentosum 1 · xeroderma pigmentosum caused by mutation in XPA · xeroderma pigmentosum group A · xeroderma pigmentosum group type A · xeroderma pigmentosum, complementation group A · xeroderma pigmentosum, complementation group type a · xeroderma pigmentosum, group A · xeroderma pigmentosum, type 1 · XP-A · XP1 · XPA · XPA xeroderma pigmentosum

Data availability: 147 ClinVar variants · 6 GenCC gene-disease records · 196 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 group A

Related subtypes (9): xeroderma pigmentosum, autosomal dominant, mild, 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

147 retrieved; paginated sample, class counts are floors:

37 uncertain significance, 35 likely pathogenic, 28 pathogenic, 16 benign, 15 pathogenic/likely pathogenic, 8 benign/likely benign, 7 conflicting classifications of pathogenicity, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1012622	NM_000380.4(XPA):c.545_546dup (p.Lys183Ter)	XPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1355854	NM_000380.4(XPA):c.717dup (p.Ile240fs)	XPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1457431	NM_000380.4(XPA):c.689dup (p.Arg231fs)	XPA	Pathogenic	criteria provided, multiple submitters, no conflicts
1457433	NM_000380.4(XPA):c.540_541del (p.Tyr181fs)	XPA	Pathogenic	criteria provided, multiple submitters, no conflicts
1709507	NM_000380.4(XPA):c.520C>T (p.Gln174Ter)	XPA	Pathogenic	criteria provided, multiple submitters, no conflicts
1805592	NM_000380.4(XPA):c.759dup (p.Asp254fs)	XPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1805601	NM_000380.4(XPA):c.640dup (p.Met214fs)	XPA	Pathogenic	criteria provided, multiple submitters, no conflicts
190207	NM_000380.4(XPA):c.545_546insTA (p.Leu182fs)	XPA	Pathogenic	criteria provided, single submitter
264684	NM_000380.4(XPA):c.390-1G>C	XPA	Pathogenic	criteria provided, multiple submitters, no conflicts
267185	NM_000380.4(XPA):c.553C>T (p.Gln185Ter)	XPA	Pathogenic	criteria provided, multiple submitters, no conflicts
267186	NM_000380.4(XPA):c.374del (p.Thr125fs)	XPA	Pathogenic	criteria provided, single submitter
2735303	NM_000380.4(XPA):c.471_472del (p.Glu159fs)	XPA	Pathogenic	criteria provided, multiple submitters, no conflicts
2735305	NM_000380.4(XPA):c.283G>A (p.Gly95Arg)	XPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3240745	NM_000380.4(XPA):c.601_605del (p.Glu201fs)	XPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3240747	NM_000380.4(XPA):c.389+1G>T	XPA	Pathogenic	criteria provided, single submitter
3596017	NM_000380.4(XPA):c.-4_1delinsGGAGT (p.Met1Leu)	XPA	Pathogenic	criteria provided, single submitter
374933	NM_000380.4(XPA):c.648_649del (p.Lys217fs)	XPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4081069	NM_000380.4(XPA):c.390-2A>G	XPA	Pathogenic	criteria provided, single submitter
4813848	NM_000380.4(XPA):c.613del (p.Glu205fs)	XPA	Pathogenic	criteria provided, single submitter
523608	NM_000380.4(XPA):c.772_785del (p.Arg258fs)	XPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
524023	NM_000380.4(XPA):c.266_267dup (p.Val90fs)	XPA	Pathogenic	criteria provided, multiple submitters, no conflicts
550646	NM_000380.4(XPA):c.555G>C (p.Gln185His)	XPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
551809	NM_000380.4(XPA):c.631C>T (p.Arg211Ter)	XPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
552532	NM_000380.4(XPA):c.732dup (p.Glu245Ter)	XPA	Pathogenic	criteria provided, single submitter
553390	NM_000380.4(XPA):c.338_339del (p.Met113fs)	XPA	Pathogenic	criteria provided, single submitter
553445	NM_000380.4(XPA):c.666dup (p.Val223fs)	XPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
553816	NM_000380.4(XPA):c.646C>T (p.Gln216Ter)	XPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
553992	NM_000380.4(XPA):c.451A>T (p.Lys151Ter)	XPA	Pathogenic	criteria provided, single submitter
554689	NM_000380.4(XPA):c.677T>A (p.Leu226Ter)	XPA	Pathogenic	criteria provided, single submitter
554759	NM_000380.4(XPA):c.459_460del (p.Cys153_Asp154delinsTer)	XPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 2 · 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
XPA	Definitive	Autosomal recessive	xeroderma pigmentosum group A	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
XPA	Orphanet:910	Xeroderma pigmentosum
XPC	Orphanet:910	Xeroderma pigmentosum

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

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	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.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 1 · 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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

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

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	2
Brodmann (1909) area 23	1
left lobe of thyroid gland	1
mucosa of stomach	1
sural nerve	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

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
XPA	1,988
XPC	1,916

Intra-cohort edges

A	B	Sources
XPA	XPC	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
XPA	P23025	18
XPC	Q01831	18

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 2 evidence-associated genes (2 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 2 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	2	253.8×	9e-05	XPA, XPC
DNA Damage Recognition in GG-NER	1	142.8×	0.014	XPC
Dual Incision in GG-NER	1	129.8×	0.014	XPA
Formation of TC-NER Pre-Incision Complex	1	105.7×	0.014	XPA
Dual incision in TC-NER	1	86.5×	0.014	XPA
SUMOylation of DNA damage response and repair proteins	1	73.2×	0.014	XPC

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
UV-damage excision repair	2	1296.3×	1e-05	XPA, XPC
nucleotide-excision repair	2	383.0×	7e-05	XPA, XPC
nucleotide-excision repair, DNA damage recognition	1	8426.0×	9e-04	XPA
DNA repair	2	63.8×	0.001	XPA, XPC
nucleotide-excision repair involved in interstrand cross-link repair	1	2808.7×	0.002	XPA
pyrimidine dimer repair by nucleotide-excision repair	1	2106.5×	0.002	XPC
response to UV-B	1	936.2×	0.003	XPC
regulation of mitotic cell cycle phase transition	1	842.6×	0.003	XPC
UV protection	1	601.9×	0.004	XPA
mitotic intra-S DNA damage checkpoint signaling	1	468.1×	0.005	XPC
response to auditory stimulus	1	366.4×	0.005	XPC
mismatch repair	1	324.1×	0.006	XPC
base-excision repair	1	234.1×	0.007	XPA
protein localization to nucleus	1	175.5×	0.009	XPA
intrinsic apoptotic signaling pathway in response to DNA damage	1	162.0×	0.009	XPA
positive regulation of transcription initiation by RNA polymerase II	1	135.9×	0.010	XPA
regulation of autophagy	1	120.4×	0.011	XPA
response to toxic substance	1	105.3×	0.012	XPA
multicellular organism growth	1	68.5×	0.017	XPA
response to oxidative stress	1	65.3×	0.017	XPA
response to xenobiotic stimulus	1	34.5×	0.030	XPC
positive regulation of DNA-templated transcription	1	14.0×	0.070	XPC

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
XPA	0	0
XPC	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
XPA	6	Binding:6

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	2	XPA, XPC

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
XPA	6	—
XPC	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.