POLH

Chr 6

DNA polymerase eta

Also known as: RAD30, RAD30A, XP-V, XPV

NCBI Gene: 5429 ENSG00000170734 UniProt: Q9Y253

This gene encodes DNA polymerase eta, which performs translesion synthesis to repair UV-damaged DNA by accurately replicating across pyrimidine dimers and other DNA lesions. Mutations cause xeroderma pigmentosum variant type, an autosomal recessive disorder characterized by extreme sun sensitivity and increased cancer risk due to defective DNA repair. The gene is highly constrained against loss-of-function variants (pLI near zero), indicating that complete loss of function is likely incompatible with normal development.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the Y family of specialized DNA polymerases. It copies undamaged DNA with a lower fidelity than other DNA-directed polymerases. However, it accurately replicates UV-damaged DNA; when thymine dimers are present, this polymerase inserts the complementary nucleotides in the newly synthesized DNA, thereby bypassing the lesion and suppressing the mutagenic effect of UV-induced DNA damage. This polymerase is thought to be involved in hypermutation during immunoglobulin class switch recombination. Mutations in this gene result in XPV, a variant type of xeroderma pigmentosum. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2014]

GeneReviews ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.84

Clinical Summary— POLH

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Gene-Disease Validity (ClinGen)

xeroderma pigmentosum variant type · 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

69 unique Pathogenic / Likely Pathogenic· 244 VUS of 663 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 — POLH

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.84LOEUF

pLI 0.000

Z-score 2.30

OE 0.57 (0.40–0.84)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.82Z-score

OE missense 0.88 (0.81–0.97)

340 obs / 385.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.57 (0.40–0.84)

0≤0.351.4

Missense OE?0.88 (0.81–0.97)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 19 / 33.3Missense obs/exp: 340 / 385.1Syn Z: 0.17

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitivePOLH-related xeroderma pigmentosum, variant typeLOFAR

This gene — mechanism propensity

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

0.7033th %ile

GOF

0.3590th %ile

LOF

0.3551th %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

663 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic48

Likely Pathogenic21

VUS244

Likely Benign245

Benign62

Conflicting23

Pathogenic

Likely Pathogenic

244

VUS

245

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	39	1	8	0	48
Likely Pathogenic	15	2	4	0	21
VUS	4	119	120	1	244
Likely Benign	1	15	87	142	245
Benign	0	2	59	1	62
Conflicting	—				23
Total	59	139	278	144	643

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

View in ClinVar →

10 pathogenic / likely-pathogenic (of 14) ClinVar copy-number / structural variants overlap POLH — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →