PCNA

protein-coding

proliferating cell nuclear antigen

Gene summary

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]

MANE transcript

NM_182649.2

Inheritance

ClinVar variants

P:1U:15B:10

Top phenotype

Ataxia-telangiectasia-like disorder 2

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr20:5,114,953-5,126,626

External References & Databases

Ensembl (ENSG00000132646)

Transcript & Mutation Effects

hg38 • Region Span ~11.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

ataxia-telangiectasia-like disorder 2SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014399

Submitter: Orphanet

ataxia-telangiectasia-like disorder 2LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014399

Submitter: Labcorp Genetics (formerly Invitae)

hereditary ataxiaLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0100309

Submitter: ClinGen

Proliferating cell nuclear antigen (*PCNA*) was first reported in relation to autosomal recessive ataxia-telangiectasia like disorder in 2014 (Baple et al., PMID: 24911150). Among the reported cases: ataxia, photosensitivity, telangiectasias, and some degree of intellectual disability have been observed in biallelic variant carriers. The phenotypic spectrum may be more diverse but more cases are needed to confirm. Only two missense variants have been associated with *PCNA*-related disease in five families across 3 publications (PMIDs: 24911150, 33426167, 36990216). Segregation of biallelic *PCNA* variants with disease is consistent across the 5 families, with every homozygous carrier being affected with similar features. The mechanism of pathogenicity is unclear but not expected to be a result of haploinsufficiency as *PCNA* knockout mice are embryonic lethal (PMID: 18854411). It is known though, that PCNA is a key protein in DNA synthesis and repair and variation in genes with similar function have been associated with disease characterized by similar features (PMID: 39622612). This gene-disease relationship is also supported by biochemical, protein interaction, and functional data in patient cells PMIDs: 8621631, 28073635, 36990216). There is evidence of altered protein stability for both variants, altered protein interaction with genes associated with similar disease features but not entirely overlapping, and that *PCNA* is involved in DNA repair. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Cerebella Ataxia GCEP on the meeting date, April 9th, 2025 (SOP Version 11).

ataxia-telangiectasia-like disorder 2LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014399

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Ataxia-telangiectasia-like disorder 2AR

Manifestation: Dermatologic; Neurologic; Oncologic; Ophthalmologic

Intervention: Oncologic

Rationale: An individual has been described with evidence of predisposition to malignancy related to sun exposure, and preventive measures and surveillance may allow prevent oncologic disease and allow early diagnosis and management

Refs: 24911150

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PCNA variants in ClinVar

4 Conditions Cataloged

not providedTotal: 11

not specifiedTotal: 10

Ataxia-telangiectasia-like disorder 2Total: 2

PCNA-related disorderTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_182649.2. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	9 clinvar	1 clinvar	11
missense		1 clinvar	11 clinvar			12
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	0	1	15	9	1	26

Highest pathogenic variant AF is 0.0000027367905

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 24 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_182649.2	RefSeq	NP_872590.1	6	MANE Select
ENST00000379143.10	Ensembl	ENSP00000368438.5	6	MANE Select
NM_002592.2	RefSeq	NP_002583.1	6	Standard
ENST00000379160.3	Ensembl	ENSP00000368458.3	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Nucleotide excision repair - Homo sapiens (human)
Cell cycle - Homo sapiens (human)
Tight junction - Homo sapiens (human)
Base excision repair - Homo sapiens (human)
HTLV-I infection - Homo sapiens (human)

Biological Process

regulation of transcription involved in G1/S transition of mitotic cell cycle
telomere maintenance
leading strand elongation
transcription-coupled nucleotide-excision repair
nucleotide-excision repair, DNA incision, 5'-to lesion

Molecular Function

purine-specific mismatch base pair DNA N-glycosylase activity
chromatin binding
damaged DNA binding
protein binding
enzyme binding

Cellular Component

nuclear chromosome, telomeric region
chromatin
nucleus
nucleoplasm
replication fork

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000379160
Coding exons: 6
Length: 11674
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.47	62	146	0.424	0.00000689	1715
Missense (PolyPhen)		7	34.729	0.20156		439
Synonymous	0.450	51	55.3	0.923	0.00000286	486
Loss of Function	3.14	0	11.5	0.00	5.68e-7	138

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Auxiliary protein of DNA polymerase delta and is involved in the control of eukaryotic DNA replication by increasing the polymerase's processibility during elongation of the leading strand. Induces a robust stimulatory effect on the 3'- 5' exonuclease and 3'-phosphodiesterase, but not apurinic- apyrimidinic (AP) endonuclease, APEX2 activities. Has to be loaded onto DNA in order to be able to stimulate APEX2. Plays a key role in DNA damage response (DDR) by being conveniently positioned at the replication fork to coordinate DNA replication with DNA repair and DNA damage tolerance pathways (PubMed:24939902). Acts as a loading platform to recruit DDR proteins that allow completion of DNA replication after DNA damage and promote postreplication repair: Monoubiquitinated PCNA leads to recruitment of translesion (TLS) polymerases, while 'Lys-63'-linked polyubiquitination of PCNA is involved in error-free pathway and employs recombination mechanisms to synthesize across the lesion. {ECO:0000269|PubMed:18719106, ECO:0000269|PubMed:19443450, ECO:0000269|PubMed:24939902}.;
Disease: DISEASE: Ataxia-telangiectasia-like disorder 2 (ATLD2) [MIM:615919]: A neurodegenerative disorder due to defects in DNA excision repair. ATLD2 is characterized by developmental delay, ataxia, sensorineural hearing loss, short stature, cutaneous and ocular telangiectasia, and photosensitivity. {ECO:0000269|PubMed:24911150}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.966

Intolerance Scores

RVIS EVS: -0.21
RVIS percentile EVS: 38.28

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.984

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium