XPA

Chr 9AR

XPA, DNA damage recognition and repair factor

Also known as: XP1, XPAC

NCBI Gene: 7507 ENSG00000136936 OMIM: 611153

This gene encodes a zinc finger protein that initiates DNA nucleotide excision repair by binding to damaged sites and serving as a scaffold to assemble the repair complex, particularly for UV-induced DNA damage. Mutations cause xeroderma pigmentosum group A, an autosomal recessive disorder characterized by extreme UV hypersensitivity and markedly increased skin cancer risk. The gene is highly constrained against loss-of-function variants (pLI near 0, LOEUF 0.97), reflecting its essential role in DNA repair.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a zinc finger protein plays a central role in nucleotide excision repair (NER), a specialized type of DNA repair. NER is responsible for repair of UV radiation-induced photoproducts and DNA adducts induced by chemical carcinogens and chemotherapeutic drugs. The encoded protein interacts with DNA and several NER proteins, acting as a scaffold to assemble the NER incision complex at sites of DNA damage. Mutations in this gene cause Xeroderma pigmentosum complementation group A (XP-A), an autosomal recessive skin disorder featuring hypersensitivity to sunlight and increased risk for skin cancer. [provided by RefSeq, Aug 2017]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.972 OMIM phenotypes

Clinical Summary— XPA

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Gene-Disease Validity (ClinGen)

xeroderma pigmentosum group A · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

114 unique Pathogenic / Likely Pathogenic· 131 VUS of 470 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — XPA

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?

0.97LOEUF

pLI 0.000

Z-score 1.65

OE 0.56 (0.34–0.97)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.35Z-score

OE missense 0.92 (0.80–1.06)

139 obs / 151.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.56 (0.34–0.97)

0≤0.351.4

Missense OE?0.92 (0.80–1.06)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 9 / 16.2Missense obs/exp: 139 / 151.0Syn Z: -0.44

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveXPA-related xeroderma pigmentosumLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.7034th %ile

GOF

0.6051th %ile

LOF

0.2871th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

470 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic58

Likely Pathogenic56

VUS131

Likely Benign175

Benign14

Conflicting11

Pathogenic

Likely Pathogenic

131

VUS

175

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	54	1	3	0	58
Likely Pathogenic	45	10	1	0	56
VUS	4	108	17	2	131
Likely Benign	0	5	61	109	175
Benign	0	1	13	0	14
Conflicting	—				11
Total	103	125	95	111	445

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

32 pathogenic / likely-pathogenic (of 37) ClinVar copy-number / structural variants overlap XPA — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →