RFC1

Chr 4AR

replication factor C subunit 1

Also known as: A1, CANVAS, MHCBFB, PO-GA, RECC1, RFC, RFC140

NCBI Gene: 5981ENSG00000035928UniProt: P35251

This gene encodes the large subunit of replication factor C, a five subunit DNA polymerase accessory protein, which is a DNA-dependent ATPase required for eukaryotic DNA replication and repair. The large subunit acts as an activator of DNA polymerases, binds to the 3' end of primers, and promotes coordinated synthesis of both strands. It may also have a role in telomere stability. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Mar 2011]

Primary Disease Associations & Inheritance

Cerebellar ataxia, neuropathy, and vestibular areflexia syndromeMIM #614575
AR
211
ClinVar variants
32
Pathogenic / LP
0.97
pLI score· haploinsufficient
4
Active trials
Clinical Summary— RFC1
🧬
Gene-Disease Validity (ClinGen)
cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.97). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
32 Pathogenic / Likely Pathogenic· 156 VUS of 211 total submissions
💊
Clinical Trials
4 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.
0.30LOEUF
pLI 0.973
Z-score 5.84
OE 0.18 (0.12–0.30)
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.
1.38Z-score
OE missense 0.84 (0.78–0.91)
502 obs / 597.0 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.0.18 (0.12–0.30)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.84 (0.78–0.91)
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: 11 / 59.6Missense obs/exp: 502 / 597.0Syn Z: -0.12

ClinVar Variant Classifications

211 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic29
Likely Pathogenic3
VUS156
Likely Benign9
Benign14
29
Pathogenic
3
Likely Pathogenic
156
VUS
9
Likely Benign
14
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
3
0
26
0
29
Likely Pathogenic
2
0
1
0
3
VUS
1
144
10
1
156
Likely Benign
0
4
1
4
9
Benign
0
4
6
4
14
Total6152449211

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

View in ClinVar →

Protein Context — Lollipop Plot

RFC1 · 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

Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome

MIM #614575

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — RFC1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS): genetic and clinical aspects.
Cortese A et al.·Pract Neurol
2022Review
Ataxia.
Zesiewicz TA·Continuum (Minneap Minn)
2025Review
Normal and pathogenic variation of RFC1 repeat expansions: implications for clinical diagnosis.
Dominik N et al.·Brain
2023
RFC1: Motifs and phenotypes.
Delforge V et al.·Rev Neurol (Paris)
2024Review
Update on Cerebellar Ataxia with Neuropathy and Bilateral Vestibular Areflexia Syndrome (CANVAS).
Dupré M et al.·Cerebellum
2021Review
Cerebellar ataxia-neuropathy-vestibular areflexia-syndrome.
Vinther-Jensen T et al.·Ugeskr Laeger
2023Review
An Update on the Adult-Onset Hereditary Cerebellar Ataxias: Novel Genetic Causes and New Diagnostic Approaches.
Rudaks LI et al.·Cerebellum
2024Review
An Updated Canvas of the RFC1-mediated CANVAS (Cerebellar Ataxia, Neuropathy and Vestibular Areflexia Syndrome).
Shukla S et al.·Mol Neurobiol
2025Review
CANVAS as example of genetic and clinical complexity of RFC1-related disorders.
Tomczuk F et al.·Neurol Neurochir Pol
2025Review
Natural History, Phenotypic Spectrum, and Discriminative Features of Multisystemic RFC1 Disease.
Traschütz A et al.·Neurology
2021Natural history
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
Bilateral Vestibular HypofunctionBilateral Vestibular DeficiencyBilateral Vestibulopathy

Long Term Outcomes After Vestibular Implantation

RECRUITING
NCT06500975Phase NAJohns Hopkins UniversityStarted 2024-12-01
Labyrinth Devices MVI™ Multichannel Vestibular Implant System
CANVAS Syndrome

Pathogenic Insights and Search for Biomarkers in RFC1-ataxia/CANVAS

RECRUITING
NCT07156214Phase NACatholic University of the Sacred HeartStarted 2024-10-14
Assessment of markers of oxidative stress in peripheral blood samples

External Resources

Links to major genomics databases and tools