RFC5

Chr 12

replication factor C subunit 5

Also known as: RFC36

NCBI Gene: 5985 ENSG00000111445 UniProt: P40937 OMIM: 600407

The RFC5 protein is the smallest subunit of the replication factor C complex, which loads proliferating cell nuclear antigen onto DNA during replication and is required for DNA synthesis by polymerases delta and epsilon. Mutations cause autosomal recessive Neurofibromatosis-like syndrome, characterized by café-au-lait spots, learning disabilities, and dysmorphic features. The gene shows low constraint to loss-of-function variation (pLI 0.0005, LOEUF 0.75), suggesting tolerance to reduced gene dosage.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes the smallest subunit of the replication factor C complex, which consists of five distinct subunits (140, 40, 38, 37, and 36 kDa) and is required for DNA replication. This subunit interacts with the C-terminal region of proliferating cell nuclear antigen and is required to open and load proliferating cell nuclear antigen onto DNA during S phase. It is a member of the AAA+ (ATPases associated with various cellular activities) ATPase family and forms a core complex with the 38 and 40 kDa subunits that possesses DNA-dependent ATPase activity. A related pseudogene has been identified on chromosome 9. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 0.75

Clinical Summary— RFC5

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 52 VUS of 92 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.75LOEUF

pLI 0.001

Z-score 2.42

OE 0.43 (0.26–0.75)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.22Z-score

OE missense 0.75 (0.66–0.86)

145 obs / 192.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.43 (0.26–0.75)

0≤0.351.4

Missense OE?0.75 (0.66–0.86)

0≤0.61.4

Synonymous OE?0.89

0≤1.21.6

LoF obs/exp: 9 / 20.9Missense obs/exp: 145 / 192.8Syn Z: 0.72

This gene — mechanism propensity

0.78top 25%

GOF

0.4579th %ile

LOF

0.2873th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

92 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

VUS52

Likely Benign3

Benign1

Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Synonymous	Total
Pathogenic	0	1	0	1
Likely Pathogenic	0	0	0	0
VUS	1	51	0	52
Likely Benign	0	1	2	3
Benign	0	0	1	1
Total	1	53	3	57

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

View in ClinVar →

14 pathogenic / likely-pathogenic (of 18) ClinVar copy-number / structural variants overlap RFC5 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →