RFC4

Chr 3AR

replication factor C subunit 4

Also known as: A1, MRMNS, RFC37

NCBI Gene: 5984ENSG00000163918UniProt: P35249

The elongation of primed DNA templates by DNA polymerase delta and DNA polymerase epsilon requires the accessory proteins proliferating cell nuclear antigen (PCNA) and replication factor C (RFC). RFC, also named activator 1, is a protein complex consisting of five distinct subunits of 140, 40, 38, 37, and 36 kD. This gene encodes the 37 kD subunit. This subunit forms a core complex with the 36 and 40 kDa subunits. The core complex possesses DNA-dependent ATPase activity, which was found to be stimulated by PCNA in an in vitro system. Alternatively spliced transcript variants encoding the same protein have been reported. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Morimoto-Ryu-Malicdan neuromuscular syndromeMIM #621010
AR
127
ClinVar variants
54
Pathogenic / LP
0.00
pLI score
1
Active trials
Clinical Summary— RFC4
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
54 Pathogenic / Likely Pathogenic· 65 VUS of 127 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.
0.90LOEUF
pLI 0.000
Z-score 1.94
OE 0.58 (0.38–0.90)
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.
-0.29Z-score
OE missense 1.06 (0.94–1.19)
211 obs / 199.6 exp
Tolerant

Tolerant to missense variation

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.0.58 (0.38–0.90)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.06 (0.94–1.19)
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.0.96
0≤1.21.6
LoF obs/exp: 14 / 24.3Missense obs/exp: 211 / 199.6Syn Z: 0.28

ClinVar Variant Classifications

127 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic46
Likely Pathogenic8
VUS65
Likely Benign6
Benign1
Conflicting1
46
Pathogenic
8
Likely Pathogenic
65
VUS
6
Likely Benign
1
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
3
1
42
0
46
Likely Pathogenic
1
1
6
0
8
VUS
0
59
6
0
65
Likely Benign
0
2
2
2
6
Benign
0
0
1
0
1
Conflicting
—1
Total463572127

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

View in ClinVar →

Protein Context — Lollipop Plot

RFC4 · 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

Morimoto-Ryu-Malicdan neuromuscular syndrome

MIM #621010

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Expanding the genetic and phenotypic landscape of replication factor C complex-related disorders: RFC4 deficiency is linked to a multisystemic disorder.
Morimoto M et al.·Am J Hum Genet
2024
Knockdown of RFC4 inhibits the cell proliferation of nasopharyngeal carcinoma in vitro and in vivo.
Guan S et al.·Front Med
2023
Comprehensive analysis of RFC4 as a potential biomarker for regulating the immune microenvironment and predicting immune therapy response in lung adenocarcinoma.
Zheng J et al.·Front Immunol
2025
RFC4 promotes the progression and growth of Oral Tongue squamous cell carcinoma in vivo and vitro.
Zhang J et al.·J Clin Lab Anal
2021
Identification and validation of a novel defined stress granule-related gene signature for predicting the prognosis of ovarian cancer via bioinformatics analysis.
Chen X et al.·Medicine (Baltimore)
2024
RFC4 Drives Pancreatic Cancer Progression: Prognostic Relevance and Functional Evidence.
Koh JW et al.·Anticancer Res
2025Functional
Roles of MARCKSL1, MCM6, RFC4, and PLAU genes in esophageal cancer and their association with radiotherapy response.
Zeng B et al.·Sci Rep
2025
Genome-wide RNAi Screening Identifies RFC4 as a Factor That Mediates Radioresistance in Colorectal Cancer by Facilitating Nonhomologous End Joining Repair.
Wang XC et al.·Clin Cancer Res
2019
RFC4 Promotes the Metastasis of Colorectal Cancer by Regulating the Wnt/β-Catenin Pathway.
Hu G et al.·Cell Biol Int
2026
Replication Factor C4 in human hepatocellular carcinoma: A potent prognostic factor associated with cell proliferation.
Chen P et al.·Biosci Trends
2021
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

External Resources

Links to major genomics databases and tools