RFC4

Chr 3AR

replication factor C subunit 4

Also known as: A1, MRMNS, RFC37

NCBI Gene: 5984 ENSG00000163918 UniProt: P35249 OMIM: 102577

RFC4 encodes the 37 kDa subunit of replication factor C, which loads proliferating cell nuclear antigen onto primed DNA during DNA replication and functions as a scaffold for complex assembly. Biallelic mutations cause Morimoto-Ryu-Malicdan neuromuscular syndrome, an autosomal recessive disorder affecting the neuromuscular system. The gene shows minimal constraint against loss-of-function variants in the general population.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

DNmechanismARLOEUF 0.901 OMIM phenotype

Clinical Summary— RFC4

⚡

Population Constraint (gnomAD)

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

📋

ClinVar Variants

11 unique Pathogenic / Likely Pathogenic· 63 VUS of 93 total submissions

💊

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?

0.90LOEUF

pLI 0.000

Z-score 1.94

OE 0.58 (0.38–0.90)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.29Z-score

OE missense 1.06 (0.94–1.19)

211 obs / 199.6 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.58 (0.38–0.90)

0≤0.351.4

Missense OE?1.06 (0.94–1.19)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 14 / 24.3Missense obs/exp: 211 / 199.6Syn Z: 0.28

This gene — mechanism propensity

0.81top 10%

GOF

0.5367th %ile

LOF

0.2678th %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

93 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic6

Likely Pathogenic5

VUS63

Likely Benign4

Benign1

Conflicting1

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	3	3	0	0	6
Likely Pathogenic	1	2	2	0	5
VUS	1	60	2	0	63
Likely Benign	0	2	0	2	4
Benign	0	0	1	0	1
Conflicting	—				1
Total	5	67	5	2	80

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

View in ClinVar →

43 pathogenic / likely-pathogenic (of 49) ClinVar copy-number / structural variants overlap RFC4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →