PCNA

Chr 20AR

proliferating cell nuclear antigen

Also known as: ATLD2

NCBI Gene: 5111ENSG00000132646UniProt: P12004

The protein encoded by this gene is found in the nucleus and is a cofactor of DNA polymerase delta. The encoded protein acts as a homotrimer and helps increase the processivity of leading strand synthesis during DNA replication. In response to DNA damage, this protein is ubiquitinated and is involved in the RAD6-dependent DNA repair pathway. Two transcript variants encoding the same protein have been found for this gene. Pseudogenes of this gene have been described on chromosome 4 and on the X chromosome. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

?Ataxia-telangiectasia-like disorder 2MIM #615919
AR
61
ClinVar variants
30
Pathogenic / LP
0.98
pLI score· haploinsufficient
12
Active trials
Clinical Summary— PCNA
🧬
Gene-Disease Validity (ClinGen)
hereditary ataxia · ARLimited

Limited evidence — not for standalone diagnostic reporting

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.98). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
30 Pathogenic / Likely Pathogenic· 20 VUS of 61 total submissions
💊
Clinical Trials
12 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
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.
0.26LOEUF
pLI 0.976
Z-score 3.14
OE 0.00 (0.00–0.26)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

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.
2.47Z-score
OE missense 0.42 (0.34–0.52)
62 obs / 146.2 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

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.0.00 (0.00–0.26)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.42 (0.34–0.52)
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.0.92
0≤1.21.6
LoF obs/exp: 0 / 11.5Missense obs/exp: 62 / 146.2Syn Z: 0.45

ClinVar Variant Classifications

61 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic27
Likely Pathogenic3
VUS20
Likely Benign8
Benign3
27
Pathogenic
3
Likely Pathogenic
20
VUS
8
Likely Benign
3
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
27
0
27
Likely Pathogenic
0
1
2
0
3
VUS
0
11
9
0
20
Likely Benign
0
0
0
8
8
Benign
0
0
1
2
3
Total012391061

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

View in ClinVar →

Protein Context — Lollipop Plot

PCNA · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

?Ataxia-telangiectasia-like disorder 2

MIM #615919

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — PCNA
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Large cell acanthoma.
Mehregan DR et al.·Int J Dermatol
2003
Structural and molecular basis of PCNA-activated FAN1 nuclease function in DNA repair.
Li F et al.·Nat Commun
2025
A thermosensitive PCNA allele underlies an ataxia-telangiectasia-like disorder.
Magrino J et al.·J Biol Chem
2023
Designed peptide binders and nanobodies as PROTAC starting points for targeted degradation of PCNA and BCL6.
Zhao S et al.·Int J Biol Macromol
2025
p21--negative regulator of the cell cycle.
Gartel AL et al.·Proc Soc Exp Biol Med
1996Review
Analysis of CDKN1C in fetal growth restriction and pregnancy loss.
Suntharalingham JP et al.·F1000Res
2019Review
A FRET-Based Assay for the Identification of PCNA Inhibitors.
Hardebeck S et al.·Int J Mol Sci
2023
RCD24, B7-H4 and PCNA expression and clinical significance in ovarian cancer.
Zheng C et al.·J BUON
2019
Clinical, histopathological and immunohistochemical study of keratoacanthoma.
Vîlcea AM et al.·Rom J Morphol Embryol
2021
Cardiac parasympathetic denervation reduces hypoxic tachycardia, baroreflex sensitivity and heart rate variability in humans.
Niewinski P et al.·Sci Rep
2025
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
2025 AHA/ACC/AANP/AAPA/ABC/ACCP/ACPM/AGS/AMA/ASPC/NMA/PCNA/SGIM Guideline for the Prevention, Detection, Evaluation and Management of High Blood Pressure in Adults: a commentary from the European Renal Best Practice (ERBP).
Kanbay M et al.·Nephrol Dial Transplant
2026
Merremia tridentata ethyl acetate extract suppresses HepG2 hepatocellular carcinoma cell proliferation via PCNA downregulation and mitochondria-mediated apoptosis.
Kasthuri K et al.·Med Oncol
2026
Structure of the human CTF18-RFC clamp loader bound to PCNA.
Briola GR et al.·Elife
2026🔓 Open Access
Phosphorylation level of the p21 PIP-box modulates interaction with PCNA in living cells.
Melle C et al.·Biochem Biophys Res Commun
2026
Screening for novel chemical scaffolds targeting PCNA identifies the Hsp90alpha inhibitor SNX-2112.
Jossart J et al.·Curr Res Struct Biol
2026🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Advanced Solid TumorMetastatic Solid TumorRefractory Solid Tumor

Safety/Efficacy Study of CID-078 in Patients With Advanced Solid Tumor Malignancies

RECRUITING
NCT06577987Phase PHASE1Circle PharmaStarted 2024-08-14
CID-078 Monotherapy
Cancer

Study of the CDK4/6 Inhibitor Abemaciclib in Solid Tumors Harboring Genetic Alterations in Genes Encoding D-Type Cyclins or Amplification of CDK4 or CDK6

RECRUITING
NCT03310879Phase PHASE2Dana-Farber Cancer InstituteStarted 2017-11-21
Abemaciclib
Breast Cancer

Long-Term Follow-Up in Women With Early Breast Cancer Three Years of More Post Primary Treatment

ACTIVE NOT RECRUITING
NCT05926024UNC Lineberger Comprehensive Cancer CenterStarted 2023-01-06
Exercise Recall Patient Reported OutcomesHealth Behavior Questionnaire (HBQ)30 Patient Reported OutcomesFunctional Assessment of Cancer Therapy-General (FACT-G) Patient Reported Outcomes
Metastatic Thyroid Gland CarcinomaUnresectable Thyroid Gland Carcinoma

Dabrafenib and Lapatinib in Treating Patients With Refractory Thyroid Cancer That Cannot Be Removed by Surgery

ACTIVE NOT RECRUITING
NCT01947023Phase PHASE1National Cancer Institute (NCI)Started 2013-09-27
Biopsy ProcedureBiospecimen CollectionComputed Tomography
Solid TumorAdvanced Solid TumorMetastatic Cancer

KPMNG Study of MOlecular Profiling Guided Therapy Based on Genomic Alterations in Advanced Solid Tumors II

RECRUITING
NCT05525858Seoul National University Bundang HospitalStarted 2022-09-28
AlectinibAtezolizumabErlotinib
CDK4/6 InhibitorBreast CancerCYP3A4 Protein, Human

Pharmacogenomic and Circulating Biomarkers for CDK4/6 Inhibitors

ENROLLING BY INVITATION
NCT07100054London Health Sciences Centre Research Institute OR Lawson Research Institute of St. Joseph'sStarted 2025-10-10
Whole gene sequencingDrug-drug interaction analysisBiomarker analysis
Hormone-receptor-positive Breast CancerHuman Epidermal Growth Factor 2 Negative Carcinoma of BreastMetastatic Breast Cancer

Palbociclib in Metastatic Breast Cancer: Gene Polymorphism-based Study in Egyptian Patients.

NOT YET RECRUITING
NCT06338644Helwan UniversityStarted 2024-07-01
Palbociclib
Cirrhosis, LiverAdvanced Liver Fibrosis

Erlotinib for Hepatocellular Carcinoma Chemoprevention

NOT YET RECRUITING
NCT04172779Phase PHASE2University of Texas Southwestern Medical CenterStarted 2026-02
erlotinib hydrochloridePlacebo
Advanced Fallopian Tube CarcinomaAdvanced Malignant Solid NeoplasmAdvanced Ovarian Carcinoma

Testing the Addition of an Anti-cancer Drug, Elimusertib (BAY 1895344) ATR Inhibitor, to the Chemotherapy Treatment (Gemcitabine) for Advanced Pancreatic and Ovarian Cancer, and Advanced Solid Tumors

ACTIVE NOT RECRUITING
NCT04616534Phase PHASE1National Cancer Institute (NCI)Started 2021-06-01
Biopsy ProcedureBiospecimen CollectionDiagnostic Imaging Testing
Breast Cancer

Elacestrant and Exemestane for Patients With Pretreated HR+/HER2- Metastatic Breast Cancer and [18F] FES-avid Lesions (COMBINE)

NOT YET RECRUITING
NCT07395336Phase PHASE2European Institute of OncologyStarted 2026-04
elacestrant and exemestane
Acute Lymphoblastic Leukemia ALL

Ribociclib in Combination With Everolimus and Dexamethasone in Relapsed ALL

ACTIVE NOT RECRUITING
NCT03740334Phase PHASE1Dana-Farber Cancer InstituteStarted 2019-01-30
RibociclibDexamethasoneEverolimus
ObesityDiabetes Mellitus, Type 2Endocrine System Diseases

Intestinal Metabolic Reprogramming as a Key Mechanism of Gastric Bypass in Humans

ACTIVE NOT RECRUITING
NCT02710370University of PittsburghStarted 2016-02

External Resources

Links to major genomics databases and tools