RFC2

Chr 7

replication factor C subunit 2

Also known as: RFC40

NCBI Gene: 5982 ENSG00000049541 UniProt: P35250 OMIM: 600404

This gene encodes the 40 kD subunit of replication factor C (RFC), a protein complex that loads proliferating cell nuclear antigen (PCNA) onto DNA during replication by DNA polymerases delta and epsilon. Biallelic mutations cause severe combined immunodeficiency with microcephaly, growth restriction, and sensitivity to DNA-damaging agents, following autosomal recessive inheritance. The gene shows low constraint against loss-of-function variants, consistent with the recessive inheritance pattern observed clinically.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the activator 1 small subunits family. The elongation of primed DNA templates by DNA polymerase delta and epsilon requires the action of the accessory proteins, proliferating cell nuclear antigen (PCNA) and replication factor C (RFC). Replication factor C, also called activator 1, is a protein complex consisting of five distinct subunits. This gene encodes the 40 kD subunit, which has been shown to be responsible for binding ATP and may help promote cell survival. Disruption of this gene is associated with Williams syndrome. Alternatively spliced transcript variants encoding distinct isoforms have been described. A pseudogene of this gene has been defined on chromosome 2. [provided by RefSeq, Jul 2013]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 0.98

Clinical Summary— RFC2

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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

38 VUS of 79 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?

0.98LOEUF

pLI 0.000

Z-score 1.64

OE 0.60 (0.39–0.98)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.15Z-score

OE missense 0.77 (0.68–0.88)

160 obs / 206.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.60 (0.39–0.98)

0≤0.351.4

Missense OE?0.77 (0.68–0.88)

0≤0.61.4

Synonymous OE?1.06

0≤1.21.6

LoF obs/exp: 12 / 19.9Missense obs/exp: 160 / 206.7Syn Z: -0.46

This gene — mechanism propensity

0.79top 25%

GOF

0.5170th %ile

LOF

0.2774th %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

79 submitted variants in ClinVar

ClinVar

Classification Summary

VUS38

Likely Benign17

Benign8

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	38	0	0	38
Likely Benign	3	2	12	17
Benign	1	3	4	8
Total	42	5	16	63

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

View in ClinVar →

165 pathogenic / likely-pathogenic (of 173) ClinVar copy-number / structural variants overlap RFC2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →