POLH

Chr 6AR

DNA polymerase eta

NCBI Gene: 5429ENSG00000170734UniProt: Q9Y253

DNA polymerase specifically involved in the DNA repair by translesion synthesis (TLS) (PubMed:10385124, PubMed:11743006, PubMed:16357261, PubMed:20388628, PubMed:24449906, PubMed:24553286, PubMed:38212351). Due to low processivity on both damaged and normal DNA, cooperates with the heterotetrameric (REV3L, REV7, POLD2 and POLD3) POLZ complex for complete bypass of DNA lesions. Inserts one or 2 nucleotide(s) opposite the lesion, the primer is further extended by the tetrameric POLZ complex. In the case of 1,2-intrastrand d(GpG)-cisplatin cross-link, inserts dCTP opposite the 3' guanine (PubMed:24449906). Particularly important for the repair of UV-induced pyrimidine dimers (PubMed:10385124, PubMed:11743006). Although inserts the correct base, may cause base transitions and transversions depending upon the context. May play a role in hypermutation at immunoglobulin genes (PubMed:11376341, PubMed:14734526). Forms a Schiff base with 5'-deoxyribose phosphate at abasic sites, but does not have any lyase activity, preventing the release of the 5'-deoxyribose phosphate (5'-dRP) residue. This covalent trapping of the enzyme by the 5'-dRP residue inhibits its DNA synthetic activity during base excision repair, thereby avoiding high incidence of mutagenesis (PubMed:14630940). Targets POLI to replication foci (PubMed:12606586)

Primary Disease Associations & Inheritance

Xeroderma pigmentosum, variant typeMIM #278750
AR
581
ClinVar variants
58
Pathogenic / LP
0.00
pLI score
1
Active trials
Clinical Summary— POLH
🧬
Gene-Disease Validity (ClinGen)
xeroderma pigmentosum variant type · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
58 Pathogenic / Likely Pathogenic· 221 VUS of 581 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.84LOEUF
pLI 0.000
Z-score 2.30
OE 0.57 (0.40–0.84)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.82Z-score
OE missense 0.88 (0.81–0.97)
340 obs / 385.1 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.57 (0.40–0.84)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.88 (0.81–0.97)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.98
0≤1.21.6
LoF obs/exp: 19 / 33.3Missense obs/exp: 340 / 385.1Syn Z: 0.17

ClinVar Variant Classifications

581 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic40
Likely Pathogenic18
VUS221
Likely Benign236
Benign50
Conflicting16
40
Pathogenic
18
Likely Pathogenic
221
VUS
236
Likely Benign
50
Benign
16
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
16
0
24
0
40
Likely Pathogenic
9
2
7
0
18
VUS
4
111
105
1
221
Likely Benign
0
11
85
140
236
Benign
0
1
49
0
50
Conflicting
—16
Total29125270141581

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

View in ClinVar →

Protein Context — Lollipop Plot

POLH · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

POLH-related xeroderma pigmentosum, variant type

definitive
ARLoss Of FunctionAbsent Gene Product, Altered Gene Product Structure
SkinCancer
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Xeroderma pigmentosum, variant type

MIM #278750

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — POLH
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing.
Girard E et al.·Int J Cancer
2019
Identification of Three Human POLH Germline Variants Defective in Complementing the UV- and Cisplatin-Sensitivity of POLH-Deficient Cells.
Yeom M et al.·Int J Mol Sci
2023
The human POLH gene is not mutated, and is expressed in a cohort of patients with basal or squamous cell carcinoma of the skin.
Flanagan AM et al.·Int J Mol Med
2007Cohort
Identification of Frameshift Variants in POLH Gene Causing Xeroderma Pigmentosum in Two Consanguineous Pakistani Families.
Zamani GY et al.·Genes (Basel)
2022
Spotlight on 'xeroderma pigmentosum'.
Fassihi H·Photochem Photobiol Sci
2013
Sunlight, Vitamin D, and Xeroderma Pigmentosum.
Martens MC et al.·Adv Exp Med Biol
2020Review
Four germline POLH variants, including two found in skin tumors, impair DNA polymerase η function and cellular tolerance to UV radiation and cisplatin.
Hong JK et al.·Chem Biol Interact
2025
Novel variants in POLH and TREM2 genes associated with a complex phenotype of xeroderma pigmentosum variant type and early-onset dementia.
Soares IFZ et al.·Mol Genet Genomic Med
2020Case report
Variants of the xeroderma pigmentosum variant gene (POLH) are associated with melanoma risk.
Di Lucca J et al.·Eur J Cancer
2009
Different germline variants in the XPA gene are associated with severe, intermediate, or mild neurodegeneration in xeroderma pigmentosum patients.
Sagun JP et al.·PLoS Genet
2024Cohort
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Metastatic Malignant Solid NeoplasmUnresectable Malignant Solid Neoplasm

Studying the Safety and Determining the Optimal Dose of Novobiocin in Patients With Tumors That Have Alterations in DNA Repair Genes

RECRUITING
NCT05687110Phase PHASE1National Cancer Institute (NCI)Started 2023-07-06
Biopsy ProcedureBiospecimen CollectionDiagnostic Imaging Testing

External Resources

Links to major genomics databases and tools