RPA1

Chr 17

replication protein A1

Also known as: HSSB, MST075, PFBMFT6, REPA1, RF-A, RP-A, RPA70

NCBI Gene: 6117ENSG00000132383UniProt: P27694

This gene encodes the largest subunit of the heterotrimeric Replication Protein A (RPA) complex, which binds to single-stranded DNA (ssDNA), forming a nucleoprotein complex that plays an important role in DNA metabolism, being involved in DNA replication, repair, recombination, telomere maintenance, and co-ordinating the cellular response to DNA damage through activation of the ataxia telangiectasia and Rad3-related protein (ATR) kinase. The nucleoprotein complex protects the single-stranded DNA from nucleases, prevents formation of secondary structures that would interfere with repair, and co-ordinates the recruitment and departure of different genome maintenance factors. This subunit contains four oligonucleotide/oligosaccharide-binding (OB) domains, though the majority of ssDNA binding occurs in two of these domains. The heterotrimeric complex has two different modes of ssDNA binding, a low-affinity and high-affinity mode, determined by which ssDNA binding domains are utilized. The different binding modes differ in the length of DNA bound and in the proteins with which it interacts, thereby playing a role in regulating different genomic maintenance pathways. [provided by RefSeq, Sep 2017]

Primary Disease Associations & Inheritance

UniProtPulmonary fibrosis, and/or bone marrow failure syndrome, telomere-related, 6
177
ClinVar variants
73
Pathogenic / LP
0.09
pLI score
2
Active trials
Clinical Summary— RPA1
🧬
Gene-Disease Validity (ClinGen)
dyskeratosis congenita and related telomere biology disorder · ADLimited

Limited evidence — not for standalone diagnostic reporting

⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.25) despite low pLI — interpret in context.
📋
ClinVar Variants
73 Pathogenic / Likely Pathogenic· 86 VUS of 177 total submissions
💊
Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available
Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
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.
0.43LOEUF
pLI 0.088
Z-score 4.34
OE 0.25 (0.16–0.43)
Moderately constrained

More LoF-intolerant than ~75% 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.
1.22Z-score
OE missense 0.82 (0.74–0.90)
292 obs / 356.7 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.0.25 (0.16–0.43)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.82 (0.74–0.90)
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.1.01
0≤1.21.6
LoF obs/exp: 10 / 39.4Missense obs/exp: 292 / 356.7Syn Z: -0.12

ClinVar Variant Classifications

177 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic65
Likely Pathogenic8
VUS86
Likely Benign7
Benign11
65
Pathogenic
8
Likely Pathogenic
86
VUS
7
Likely Benign
11
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
2
63
0
65
Likely Pathogenic
0
0
8
0
8
VUS
0
69
17
0
86
Likely Benign
0
3
0
4
7
Benign
0
1
6
4
11
Total075948177

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

View in ClinVar →

Protein Context — Lollipop Plot

RPA1 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

📖
GeneReview available — RPA1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Gain-of-function mutations in RPA1 cause a syndrome with short telomeres and somatic genetic rescue.
Sharma R et al.·Blood
2022
RPA1, RFC1, and POLE Expression in Clear Cell Renal Cell Carcinoma: Immune and Clinical Relevance.
Gola M et al.·Anticancer Res
2025
Homologous Recombination Deficiency: Cancer Predispositions and Treatment Implications.
Toh M et al.·Oncologist
2021Review
The heterogeneity of genomic alterations, metastatic patterns and immune microenvironment in metastatic ovarian cancer originating from colorectal cancer.
Chen C et al.·Front Immunol
2025
Single-cell transcriptomic and m6A methylation analyses reveal platelet-mediated immune regulatory mechanisms in sepsis.
Qian W et al.·Front Immunol
2025Functional
CDC20 Holds Novel Regulation Mechanism in RPA1 during Different Stages of DNA Damage to Induce Radio-Chemoresistance.
Gao Y et al.·Int J Mol Sci
2024Functional
Increased RPA1 gene dosage affects genomic stability potentially contributing to 17p13.3 duplication syndrome.
Outwin E et al.·PLoS Genet
2011
Ailanthone: A multi-targeting Quassinoid from Ailanthus altissima for broad-spectrum cancer therapy - a comprehensive review of mechanisms, pharmacokinetics, and clinical prospects.
Huang Y et al.·J Ethnopharmacol
2026Review
FAM35A/SHLD2/RINN2: A novel determinant of double strand break repair pathway choice and genome stability in cancer.
Fackrell K et al.·Environ Mol Mutagen
2020Review
Long Non-coding RNA and mRNA Co-expression Network Reveals Novel Players in Pleomorphic Xanthoastrocytoma.
Dandapath I et al.·Mol Neurobiol
2022
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
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
Lymphoma, Non-HodgkinMultiple MyelomaAdvanced Solid Tumors

TAPUR: Testing the Use of Food and Drug Administration (FDA) Approved Drugs That Target a Specific Abnormality in a Tumor Gene in People With Advanced Stage Cancer

RECRUITING
NCT02693535Phase PHASE2American Society of Clinical OncologyStarted 2016-03-14
PalbociclibSunitinibTemsirolimus

External Resources

Links to major genomics databases and tools