RFC1

Summary

RFC1 (replication factor C subunit 1, HGNC:9969) is a protein-coding gene on chromosome 4p14, encoding Replication factor C subunit 1 (P35251). Subunit of the replication factor C (RFC) complex which acts during elongation of primed DNA templates by DNA polymerases delta and epsilon, and is necessary for ATP-dependent loading of proliferating cell nuclear antigen (PCNA) onto primed DNA.

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.

Source: NCBI Gene 5981 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 12
• Clinical variants (ClinVar): 226 total — 13 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 41
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_002913

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9969
Approved symbol	RFC1
Name	replication factor C subunit 1
Location	4p14
Locus type	gene with protein product
Status	Approved
Aliases	A1, PO-GA, RFC140, MHCBFB
Ensembl gene	ENSG00000035928
Ensembl biotype	protein_coding
OMIM	102579
Entrez	5981

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 15 protein_coding, 7 protein_coding_CDS_not_defined, 3 retained_intron, 1 nonsense_mediated_decay

ENST00000349703, ENST00000381897, ENST00000418436, ENST00000502706, ENST00000502991, ENST00000503784, ENST00000504554, ENST00000504849, ENST00000504974, ENST00000505077, ENST00000509084, ENST00000510783, ENST00000512275, ENST00000512726, ENST00000512881, ENST00000514572, ENST00000906183, ENST00000906184, ENST00000906185, ENST00000906186, ENST00000923042, ENST00000923043, ENST00000923045, ENST00000923046, ENST00000967836, ENST00000967837

RefSeq mRNA: 4 — MANE Select: NM_002913 NM_001204747, NM_001363495, NM_001363496, NM_002913

CCDS: CCDS3450, CCDS56329

Canonical transcript exons

ENST00000349703 — 25 exons

Exon	Start	End
ENSE00001077241	39306592	39306701
ENSE00001077249	39287456	39288844
ENSE00001077252	39304814	39304928
ENSE00001077254	39303060	39303151
ENSE00001077263	39300260	39300414
ENSE00001077264	39300021	39300138
ENSE00001077269	39312752	39312931
ENSE00002063495	39366239	39366362
ENSE00003500039	39311445	39311549
ENSE00003501838	39291639	39291852
ENSE00003513584	39289848	39290039
ENSE00003514776	39327524	39327756
ENSE00003528465	39302500	39302595
ENSE00003530730	39321287	39321374
ENSE00003536244	39326563	39326640
ENSE00003553611	39295614	39295759
ENSE00003559871	39308636	39309032
ENSE00003564911	39351348	39351476
ENSE00003567238	39320383	39320669
ENSE00003567720	39342345	39342467
ENSE00003603308	39302737	39302874
ENSE00003644711	39345401	39345476
ENSE00003644768	39323340	39323417
ENSE00003678785	39316915	39317022
ENSE00003681980	39302278	39302376

Expression profiles

Bgee: expression breadth ubiquitous, 278 present calls, max score 98.38.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 40.4389 / max 1377.9470, expressed in 1796 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
51839	40.3939	1796
51837	0.0450	13

Top tissues by expression

292 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	98.38	gold quality
ventricular zone	UBERON:0003053	96.75	gold quality
adrenal tissue	UBERON:0018303	95.46	gold quality
sural nerve	UBERON:0015488	95.20	gold quality
body of pancreas	UBERON:0001150	94.91	gold quality
colonic epithelium	UBERON:0000397	94.16	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	93.93	gold quality
ganglionic eminence	UBERON:0004023	93.10	gold quality
pancreas	UBERON:0001264	92.60	gold quality
bone marrow cell	CL:0002092	92.14	gold quality
embryo	UBERON:0000922	91.89	gold quality
right adrenal gland cortex	UBERON:0035827	91.89	gold quality
tonsil	UBERON:0002372	91.84	gold quality
left ovary	UBERON:0002119	91.77	gold quality
stromal cell of endometrium	CL:0002255	91.69	gold quality
right adrenal gland	UBERON:0001233	91.57	gold quality
mucosa of stomach	UBERON:0001199	91.26	gold quality
metanephros cortex	UBERON:0010533	91.20	gold quality
left adrenal gland	UBERON:0001234	91.18	gold quality
cortical plate	UBERON:0005343	91.15	gold quality
right ovary	UBERON:0002118	91.08	gold quality
islet of Langerhans	UBERON:0000006	91.07	gold quality
adrenal gland	UBERON:0002369	90.94	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	90.76	gold quality
left adrenal gland cortex	UBERON:0035825	90.75	gold quality
body of uterus	UBERON:0009853	90.58	gold quality
right lung	UBERON:0002167	90.54	gold quality
ovary	UBERON:0000992	90.37	gold quality
ectocervix	UBERON:0012249	90.32	gold quality
upper lobe of left lung	UBERON:0008952	90.18	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	14.51

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AHR, SP1, SP3, ZBED1

miRNA regulators (miRDB)

61 targeting RFC1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3617-3P	99.98	67.86	918
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-493-5P	99.96	72.47	2382
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-518A-5P	99.70	69.01	2209
HSA-MIR-527	99.70	69.01	2209
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-587	99.64	70.86	2611

Literature-anchored findings (GeneRIF, showing 40)

• interaction with histone deacetylase HDAC1 (PMID:12045192)
• RFC (p140) has an important role as a regulator of transcription and NF-kappaB activity (PMID:12509469)
• destabilization of the RF-C complex by CDKs may inactivate the RF-C complex at the end of S phase (PMID:12947101)
• NMR resonance assignments of the BRCT region of the large subunit (PMID:15772763)
• Ctf18-RFC interacts physically with pol eta, which allows DNA replication forks to overcome interference by various template structures, including damaged DNA and DNA-protein complexes that maintain chromosome cohesion (PMID:17545166)
• Data show that replication factor C (RFC), via several stimulatory motifs per molecule, potently activates flap endonuclease 1 (FEN1), making RFC a critical partner with FEN1 for the processing of eukaryotic Okazaki fragments. (PMID:19208620)
• a mutant version of hLigI, which mimics the hyperphosphorylated M-phase form of hLigI, does not interact with and is not inhibited by RFC, demonstrating that inhibition of ligation is dependent upon the interaction between hLigI and RFC (PMID:19223468)
• analysis of the DNA-bound BRCA1 C-terminal region structure from human replication factor C p140 and model of the protein-DNA complex (PMID:20081198)
• Small interfering RNA-mediated knockdown of RFC1 impairs upstream removal of UV lesions and abrogates the downstream recruitment of DNA polymerase delta. (PMID:20713449)
• We identified a variant in each of 3 genes (RFC1, SCN1A, ANPEP) potentially implicated in susceptibility to severe neurological complications in West Nile Virus disease. (PMID:21881118)
• report that the large subunit (RFC1) of replication factor C is cleaved in Hutchinson-Gilford progeria syndrome cells, leading to the production of a truncated RFC1 of ~ 75 kDa (PMID:22168243)
• phosphorylation of serine 51 on hLigI plays a critical role in regulating the interaction between hLigI and RFC, which is required for efficient DNA replication and repair. (PMID:22952233)
• RFC depletion had a negative impact on LANA’s ability to replicate and maintain viral DNA in cells containing artificial KSHV episomes or in infected cells, leading to loss of virus. (PMID:25071216)
• Human CTF18-RFC clamp-loader complexed with non-synthesising POLE efficiently loads the PCNA sliding clamp. (PMID:28199690)
• Regulation of HLTF-mediated PCNA polyubiquitination by RFC and PCNA monoubiquitination levels determines choice of damage tolerance pathway. (PMID:30335157)
• Biallelic AAGGG expansion in RFC1 is a frequent cause of late-onset ataxia. (PMID:30926972)
• Recessively inherited intronic repeat expansion [(AAGGG)exp] in the gene encoding Replication Factor C1 Causes cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome. (PMID:31230722)
• Long-read sequencing identifies the pathogenic nucleotide repeat expansion in RFC1 in a Japanese case of CANVAS. (PMID:32066831)
• No biallelic intronic AAGGG repeat expansion in RFC1 was found in patients with late-onset ataxia and MSA. (PMID:32151945)
• RFC1 Intronic Repeat Expansions Absent in Pathologically Confirmed Multiple Systems Atrophy. (PMID:32333430)
• RFC1 repeat expansion in Japanese patients with late-onset cerebellar ataxia. (PMID:32694621)
• A Maori specific RFC1 pathogenic repeat configuration in CANVAS, likely due to a founder allele. (PMID:32851396)
• Clinical spectrum of the pentanucleotide repeat expansion in the RFC1 gene in ataxia syndromes. (PMID:32873692)
• Biallelic Intronic AAGGG Expansion of RFC1 is Related to Multiple System Atrophy. (PMID:32939785)
• A novel RFC1 repeat motif (ACAGG) in two Asia-Pacific CANVAS families. (PMID:33103729)
• Natural History, Phenotypic Spectrum, and Discriminative Features of Multisystemic RFC1 Disease. (PMID:33495376)
• Biallelic RFC1-expansion in a French multicentric sporadic ataxia cohort. (PMID:33666721)
• Biallelic RFC1 pentanucleotide repeat expansions in Greek patients with late-onset ataxia. (PMID:33745133)
• CANVAS: A New Genetic Entity in the Otorhinolaryngologist’s Differential Diagnosis. (PMID:33940977)
• RFC1 expansions are a common cause of idiopathic sensory neuropathy. (PMID:33969391)
• Investigating RFC1 expansions in sporadic amyotrophic lateral sclerosis. (PMID:34537679)
• RFC1 nonsense and frameshift variants cause CANVAS: clues for an unsolved pathophysiology. (PMID:35883251)
• New Cerebellar Ataxia, Neuropathy, Vestibular Areflexia Syndrome cases are caused by the presence of a nonsense variant in compound heterozygosity with the pathogenic repeat expansion in the RFC1 gene. (PMID:36250766)
• Truncating Variants in RFC1 in Cerebellar Ataxia, Neuropathy, and Vestibular Areflexia Syndrome. (PMID:36289003)
• Association of biallelic RFC1 expansion with early-onset Parkinson’s disease. (PMID:36705320)
• Shaking Up Ataxia: FGF14 and RFC1 Repeat Expansions in Affected and Unaffected Members of a Chilean Family. (PMID:37246629)
• Can CANVAS due to RFC1 biallelic expansions present with pure ataxia? (PMID:37414537)
• Normal and pathogenic variation of RFC1 repeat expansions: implications for clinical diagnosis. (PMID:37450567)
• Frequency and Phenotype of RFC1 Repeat Expansions in Bilateral Vestibulopathy. (PMID:37460231)
• CANVAS-related RFC1 mutations in patients with immune-mediated neuropathy. (PMID:37853169)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	rfc1	ENSDARG00000054799
mus_musculus	Rfc1	ENSMUSG00000029191
rattus_norvegicus	Rfc1	ENSRNOG00000002855
drosophila_melanogaster	Gnf1	FBGN0004913
caenorhabditis_elegans		WBGENE00004337

Protein

Protein identifiers

Replication factor C subunit 1 — P35251 (reviewed: P35251)

Alternative names: Activator 1 140 kDa subunit, Activator 1 large subunit, Activator 1 subunit 1, DNA-binding protein PO-GA, Replication factor C 140 kDa subunit, Replication factor C large subunit

All UniProt accessions (5): D6RAD2, E0CX09, P35251, H0Y8U4, H0Y9P8

UniProt curated annotations — full annotation on UniProt →

Function. Subunit of the replication factor C (RFC) complex which acts during elongation of primed DNA templates by DNA polymerases delta and epsilon, and is necessary for ATP-dependent loading of proliferating cell nuclear antigen (PCNA) onto primed DNA. This subunit binds to the primer-template junction. Binds the PO-B transcription element as well as other GA rich DNA sequences. Can bind single- or double-stranded DNA.

Subunit / interactions. Large subunit of the RFC complex, an heteropentameric complex consisting of RFC1 and four small subunits RFC2, RFC3, RFC4 and RFC5; the RFC complex interacts with PCNA and the interaction involves RFC1.

Subcellular location. Nucleus.

Tissue specificity. Wide tissue distribution. Undetectable in placental tissue.

Disease relevance. Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) [MIM:614575] An autosomal recessive neurologic disease characterized by imbalance, cerebellar ataxia, impaired vestibular function, and non-length-dependent sensory deficit. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by intronic AAGGG repeat expansions in intron 2.

Miscellaneous. Alternative use of an acceptor site.

Similarity. Belongs to the activator 1 large subunit family.

Isoforms (2)

UniProt ID	Names	Canonical?
P35251-1	1	yes
P35251-2	2

RefSeq proteins (4): NP_001191676, NP_001350424, NP_001350425, NP_002904* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001357	BRCT_dom	Domain
IPR003593	AAA+_ATPase	Domain
IPR003959	ATPase_AAA_core	Domain
IPR008921	DNA_pol3_clamp-load_cplx_C	Homologous_superfamily
IPR012178	RFC1	Family
IPR013725	DNA_replication_fac_RFC1_C	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR036420	BRCT_dom_sf	Homologous_superfamily
IPR047854	RFC_lid	Domain

Pfam: PF00004, PF00533, PF08519, PF25361

Enzyme classification (BRENDA):

• EC 3.6.4.B8 — (BRENDA: organisms, substrates, inhibitors, Km, kcat entries)

UniProt features (101 total): helix 30, modified residue 20, strand 13, compositionally biased region 11, sequence conflict 6, turn 6, sequence variant 5, region of interest 4, chain 1, domain 1, binding site 1, cross-link 1, splice variant 1, short sequence motif 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
6VVO	ELECTRON MICROSCOPY	3.4
2EBU	SOLUTION NMR
2K6G	SOLUTION NMR
2K7F	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P35251-F1	61.52	0.16

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (1): 650–657

Post-translational modifications (21): 67, 69, 71, 73, 108, 110, 156, 161, 163, 164, 173, 190, 253, 281, 283, 312, 368, 537, 1104, 1106 …

Function

Pathways and Gene Ontology

Reactome pathways

14 pathways

ID	Pathway
R-HSA-110312	Translesion synthesis by REV1
R-HSA-110314	Recognition of DNA damage by PCNA-containing replication complex
R-HSA-110320	Translesion Synthesis by POLH
R-HSA-174411	Polymerase switching on the C-strand of the telomere
R-HSA-5651801	PCNA-Dependent Long Patch Base Excision Repair
R-HSA-5655862	Translesion synthesis by POLK
R-HSA-5656121	Translesion synthesis by POLI
R-HSA-5656169	Termination of translesion DNA synthesis
R-HSA-5685942	HDR through Homologous Recombination (HRR)
R-HSA-5696397	Gap-filling DNA repair synthesis and ligation in GG-NER
R-HSA-5696400	Dual Incision in GG-NER
R-HSA-6782135	Dual incision in TC-NER
R-HSA-6782210	Gap-filling DNA repair synthesis and ligation in TC-NER
R-HSA-69091	Polymerase switching

MSigDB gene sets: 389 (showing top): GOBP_RNA_TEMPLATED_DNA_BIOSYNTHETIC_PROCESS, GOBP_CHROMOSOME_ORGANIZATION, REACTOME_DNA_REPLICATION, E2F_Q4_01, RRAGTTGT_UNKNOWN, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GRUETZMANN_PANCREATIC_CANCER_DN, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, ENK_UV_RESPONSE_KERATINOCYTE_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_TELOMERE_MAINTENANCE_VIA_TELOMERE_LENGTHENING, GOBP_TELOMERE_ORGANIZATION, KAUFFMANN_DNA_REPAIR_GENES, AMIT_EGF_RESPONSE_480_MCF10A

GO Biological Process (7): negative regulation of transcription by RNA polymerase II (GO:0000122), DNA-templated DNA replication (GO:0006261), DNA repair (GO:0006281), telomere maintenance via telomerase (GO:0007004), positive regulation of DNA-templated transcription (GO:0045893), DNA replication (GO:0006260), negative regulation of DNA-templated transcription (GO:0045892)

GO Molecular Function (12): DNA binding (GO:0003677), DNA clamp loader activity (GO:0003689), double-stranded DNA binding (GO:0003690), ATP binding (GO:0005524), enzyme activator activity (GO:0008047), ATP hydrolysis activity (GO:0016887), protein domain specific binding (GO:0019904), sequence-specific DNA binding (GO:0043565), DNA clamp unloader activity (GO:0061860), DNA-binding transcription factor binding (GO:0140297), nucleotide binding (GO:0000166), protein binding (GO:0005515)

GO Cellular Component (7): nucleus (GO:0005634), nucleoplasm (GO:0005654), DNA replication factor C complex (GO:0005663), Elg1 RFC-like complex (GO:0031391), extracellular exosome (GO:0070062), chromosome (GO:0005694), protein-containing complex (GO:0032991)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
Translesion synthesis by Y family DNA polymerases bypasses lesions on DNA template	5
Global Genome Nucleotide Excision Repair (GG-NER)	2
Transcription-Coupled Nucleotide Excision Repair (TC-NER)	2
DNA Damage Bypass	1
Telomere C-strand (Lagging Strand) Synthesis	1
Resolution of AP sites via the multiple-nucleotide patch replacement pathway	1
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	1
Leading Strand Synthesis	1
Lagging Strand Synthesis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA binding	4
DNA metabolic process	2
DNA-templated transcription	2
regulation of DNA-templated transcription	2
ATP-dependent activity, acting on DNA	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
DNA replication	1
DNA damage response	1
telomerase activity	1
RNA-templated DNA biosynthetic process	1
telomere maintenance via telomere lengthening	1
telomere-telomerase complex assembly	1
positive regulation of RNA biosynthetic process	1
DNA biosynthetic process	1
negative regulation of RNA biosynthetic process	1
nucleic acid binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
catalytic activity	1
enzyme regulator activity	1
molecular function activator activity	1
ribonucleoside triphosphate phosphatase activity	1
ATP-dependent activity	1
protein binding	1
transcription factor binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular anatomical structure	1
replication fork	1
protein-containing complex	1
chromosome	1
catalytic complex	1
extracellular vesicle	1
intracellular membraneless organelle	1
cellular_component	1

Protein interactions and networks

STRING

1693 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RFC1	RFC3	P40938	918
RFC1	RFC4	P35249	874
RFC1	RFC5	P40937	833
RFC1	RFC2	P32846	733
RFC1	TMEM156	Q8N614	576
RFC1	LIG1	P18858	553
RFC1	MSH6	P52701	547
RFC1	FXN	Q16595	534
RFC1	RAD17	O75943	528
RFC1	MSH2	P43246	525
RFC1	MLH1	P40692	507
RFC1	DAB1	O75553	506
RFC1	SMIM14	Q96QK8	498
RFC1	ATM	Q13315	481
RFC1	RPA1	P27694	474

IntAct

148 interactions, top by confidence:

A	B	Type	Score
RFC4	RFC2	psi-mi:“MI:0914”(association)	0.810
RNF146	TNKS	psi-mi:“MI:0914”(association)	0.790
RFC5	RAD17	psi-mi:“MI:0914”(association)	0.730
RFC4	RAD17	psi-mi:“MI:0914”(association)	0.730
RFC1	RFC4	psi-mi:“MI:0914”(association)	0.710
RFC1	RFC4	psi-mi:“MI:0915”(physical association)	0.710
PTK2	TGFB1I1	psi-mi:“MI:0914”(association)	0.680
RFC2	RFC1	psi-mi:“MI:0915”(physical association)	0.640
NPM1	MPHOSPH10	psi-mi:“MI:0914”(association)	0.610
PCNA	RFC4	psi-mi:“MI:0914”(association)	0.530
MAGEB2	POLRMT	psi-mi:“MI:0914”(association)	0.530
RRP8	MAGEB2	psi-mi:“MI:0914”(association)	0.530
AFG2A	RFC1	psi-mi:“MI:0915”(physical association)	0.500
DDX21	MED19	psi-mi:“MI:2364”(proximity)	0.480
ESR2	FBLL1	psi-mi:“MI:0914”(association)	0.460
AFG2B	RFC1	psi-mi:“MI:0914”(association)	0.460
H3C1	SMCHD1	psi-mi:“MI:2364”(proximity)	0.410
SMC1A	RFC1	psi-mi:“MI:0915”(physical association)	0.400
OXR1	RFC1	psi-mi:“MI:0915”(physical association)	0.400
	RFC1	psi-mi:“MI:0915”(physical association)	0.400
RFC1	SSBP3	psi-mi:“MI:0915”(physical association)	0.370
RFC1	ZSCAN1	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (343): RFC1 (Affinity Capture-MS), RFC1 (Affinity Capture-MS), RFC1 (Affinity Capture-MS), RFC1 (Affinity Capture-MS), GLYR1 (Co-fractionation), PCNA (Co-fractionation), PDS5A (Co-fractionation), RACGAP1 (Co-fractionation), RFC1 (Co-fractionation), RFC2 (Co-fractionation), RFC3 (Co-fractionation), RFC4 (Co-fractionation), RFC5 (Co-fractionation), SMC1A (Co-fractionation), SMC2 (Co-fractionation)

ESM2 similar proteins: A0A1P8ASY1, A3EWL3, A4PBL4, B9EUM5, B9FL70, B9G8P1, F4HZF0, F4I9Q5, F4IL57, F4J2M6, F4JAA5, L0N7N1, O09053, O70445, O81635, O93530, P35251, P39875, P45951, Q0IMS9, Q0PCS3, Q10MN5, Q14191, Q3YK19, Q5SXJ3, Q6JDV7, Q6P158, Q7X7H4, Q7Y1C4, Q7Y1C5, Q803U7, Q8L7Y8, Q8L840, Q8W1Y3, Q941I6, Q99728, Q9C6G0, Q9FT70, Q9FT72, Q9I920

Diamond homologs: A0B6D7, A1RSA2, A1RSA3, A1RV38, A1RWU6, A1RWU7, A2BL93, A2SQR6, A2SQT3, A3CTR4, A3CUX9, A3DNV8, A3DNV9, A3MS27, A3MS28, A4FZ74, A4FZL6, A4WGV2, A4WLY0, A5UMF4, A6URV8, A6US36, A6UWR5, A6VIW1, A6VJ61, A7I781, A8AC24, A9A6K6, A9A6N2, B0R601, B1YC69, B9LPV1, C3MQ13, C3MVD2, C3N5N1, C3NE95, C3NHF4, C4KHA7, O26342, O28219

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
CDK1	“down-regulates activity”	RFC1	phosphorylation
RFC1	“form complex”	“RF-C complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 149 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Translesion synthesis by REV1	5	34.6×	3e-05
Translesion synthesis by POLI	5	32.6×	4e-05
Translesion synthesis by POLK	5	30.8×	4e-05
Translesion Synthesis by POLH	5	29.2×	5e-05
PCNA-Dependent Long Patch Base Excision Repair	5	25.2×	7e-05
Gap-filling DNA repair synthesis and ligation in GG-NER	5	21.3×	1e-04
Recognition of DNA damage by PCNA-containing replication complex	5	18.5×	2e-04
Impaired BRCA2 binding to RAD51	6	18.0×	7e-05

GO biological processes:

GO term	Partners	Fold	FDR
ribosomal large subunit biogenesis	7	23.9×	8e-06
ribosomal small subunit biogenesis	10	17.5×	3e-07
skeletal muscle cell differentiation	5	13.2×	4e-03
cytoplasmic translation	8	11.4×	1e-04
cellular response to UV	5	11.4×	6e-03
negative regulation of translation	7	10.6×	7e-04
rRNA processing	8	8.7×	7e-04
nucleosome assembly	7	7.6×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

226 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	13
Likely pathogenic	2
Uncertain significance	149
Likely benign	10
Benign	13

Top pathogenic / likely-pathogenic (15)

Variant ID	HGVS	Classification
1333160	(AAGGG)exp	Pathogenic
1809808	NC_000004.11:g.39350045_39350099delinsAAGGG[(141_831)]	Pathogenic
2577534	NM_002913.5(RFC1):c.1162C>T (p.Arg388Ter)	Pathogenic
2577535	NM_002913.5(RFC1):c.575del (p.Asn192fs)	Pathogenic
2577536	NM_002913.5(RFC1):c.2535+2T>C	Pathogenic
2577537	NM_002913.5(RFC1):c.2690+1G>A	Pathogenic
3370519	RFC1, (ACAGG)n REPEAT EXPANSION	Pathogenic
4531160	RFC1, (AGGGC)n AND (AAGGC)n REPEAT EXPANSION	Pathogenic
625839	NC_000004.12:g.39348425AARRG[(400_2000)]	Pathogenic
625876	NC_000004.11:g.39350045_39350099delinsAAGGG[(400_2000)]	Pathogenic
625877	NC_000004.12:g.39348425_39348479delinsAAAGG[400_2000]	Pathogenic
986302	NC_000004.12:g.39348425AAAGG[10_25]AAGGG[n]	Pathogenic
997970	NC_000004.12:g.39348425AAGGG[(400_2000)]	Pathogenic
3341312	NM_002913.5(RFC1):c.1255del (p.Glu419fs)	Likely pathogenic
3341313	NM_002913.5(RFC1):c.2111-1G>C	Likely pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

7619 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:39302511:C:G	D810H	0.999
4:39302824:G:C	C752W	0.999
4:39304893:A:C	S678R	0.999
4:39304893:A:T	S678R	0.999
4:39304895:T:G	S678R	0.999
4:39306608:G:T	A661D	0.999
4:39306623:C:T	G656D	0.999
4:39306624:C:G	G656R	0.999
4:39306629:C:T	G654D	0.999
4:39306638:C:T	G651D	0.999
4:39306639:C:G	G651R	0.999
4:39312761:C:A	K458N	0.999
4:39312761:C:G	K458N	0.999
4:39312789:A:T	V449D	0.999
4:39312792:A:G	L448P	0.999
4:39312813:A:T	V441D	0.999
4:39295743:A:T	V943D	0.998
4:39295745:A:C	S942R	0.998
4:39295745:A:T	S942R	0.998
4:39295747:T:G	S942R	0.998
4:39295759:C:G	A938P	0.998
4:39300041:A:G	W931R	0.998
4:39300041:A:T	W931R	0.998
4:39300098:C:G	A912P	0.998
4:39300299:A:T	V885D	0.998
4:39302363:A:G	L818P	0.998
4:39302510:T:A	D810V	0.998
4:39302510:T:G	D810A	0.998
4:39302771:A:G	L770P	0.998
4:39302779:A:C	C767W	0.998

dbSNP variants (sampled 300 via entrez): RS1000028373 (4:39317701 T>C), RS1000055739 (4:39331188 T>A,C), RS1000066643 (4:39320206 A>G), RS1000089352 (4:39362966 G>A), RS1000195076 (4:39324537 T>C), RS1000224783 (4:39324898 G>C), RS1000239637 (4:39368305 G>C), RS1000393343 (4:39361918 A>C,G), RS1000442745 (4:39317680 C>G), RS1000445636 (4:39362164 A>C), RS1000457701 (4:39343543 T>C), RS1000460817 (4:39356182 C>A,G,T), RS1000463076 (4:39324911 C>T), RS1000473308 (4:39309750 T>C), RS1000491127 (4:39331623 C>A)

Disease associations

OMIM: gene MIM:102579 | disease phenotypes: MIM:608088, MIM:614575, MIM:168600

GenCC curated gene-disease

Disease	Classification	Inheritance
cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome	Strong	Autosomal recessive
cerebellar ataxia, neuropathy, and vestibular areflexia syndrome	Moderate	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome	Definitive	AR

Mondo (5): cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (MONDO:0044720), late-onset Parkinson disease (MONDO:0008199), Parkinson disease (MONDO:0005180), hereditary breast ovarian cancer syndrome (MONDO:0003582), (MONDO:0013809)

Orphanet (5): Cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (Orphanet:504476), Hereditary late-onset Parkinson disease (Orphanet:411602), Hereditary breast and/or ovarian cancer syndrome (Orphanet:145), Hereditary sensory and autonomic neuropathy type 1B (Orphanet:139564), NON RARE IN EUROPE: Parkinson disease (Orphanet:319705)

HPO phenotypes

41 total (30 of 41 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000364	Hearing abnormality
HP:0000407	Sensorineural hearing impairment
HP:0000639	Nystagmus
HP:0000640	Gaze-evoked nystagmus
HP:0000648	Optic atrophy
HP:0000750	Delayed speech and language development
HP:0001151	Impaired horizontal smooth pursuit
HP:0001152	Saccadic smooth pursuit interruptions
HP:0001251	Ataxia
HP:0001260	Dysarthria
HP:0001265	Hyporeflexia
HP:0001272	Cerebellar atrophy
HP:0001284	Areflexia
HP:0001310	Dysmetria
HP:0002066	Gait ataxia
HP:0002070	Limb ataxia
HP:0002073	Progressive cerebellar ataxia
HP:0002075	Dysdiadochokinesis
HP:0002080	Intention tremor
HP:0002172	Postural instability
HP:0002403	Positive Romberg sign
HP:0002460	Distal muscle weakness
HP:0002494	Abnormal rapid eye movement sleep
HP:0002495	Impaired vibratory sensation
HP:0002828	Multiple joint contractures
HP:0003438	Absent Achilles reflex
HP:0003447	Axonal loss
HP:0003487	Babinski sign
HP:0003581	Adult onset

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST004602_147	Mean corpuscular volume	4.000000e-13
GCST004630_137	Mean corpuscular hemoglobin	2.000000e-12
GCST007798_64	Asthma	3.000000e-07
GCST007799_16	Asthma (adult onset)	1.000000e-06
GCST90000025_264	Appendicular lean mass	3.000000e-12
GCST90002385_246	High light scatter reticulocyte count	2.000000e-11
GCST90002386_575	High light scatter reticulocyte percentage of red cells	2.000000e-10
GCST90002390_205	Mean corpuscular hemoglobin	2.000000e-26
GCST90002392_649	Mean corpuscular volume	6.000000e-31
GCST90002396_269	Mean reticulocyte volume	1.000000e-25
GCST90002397_4	Mean spheric corpuscular volume	8.000000e-32
GCST90002405_35	Reticulocyte count	1.000000e-09

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004527	mean corpuscular hemoglobin
EFO:1002011	adult onset asthma
EFO:0004980	appendicular lean mass
EFO:0007986	reticulocyte count
EFO:0010701	mean reticulocyte volume

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D061325	Hereditary Breast and Ovarian Cancer Syndrome	C04.588.180.483; C04.588.322.455.431; C04.700.517; C12.050.351.500.056.630.705.431; C12.050.351.937.418.685.431; C12.100.250.056.630.705.431; C12.900.418.685.431; C16.320.700.517; C17.800.090.500.483; C19.344.410.431; C19.391.630.705.431
D010300	Parkinson Disease	C10.228.140.079.862.500; C10.228.662.600.400; C10.574.928.750
C564296	Neuropathy, Hereditary Sensory And Autonomic, Type I, With Cough And Gastroesophageal Reflux (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5725133 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,538

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.30	IC50	50	nM	MOLIBRESIB
7.27	Kd	54	nM	MOLIBRESIB
6.88	Kd	132.3	nM	CHEMBL3752910
6.88	ED50	132.3	nM	CHEMBL3752910

PubChem BioAssay actives

3 with measured affinity, of 9 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2178732: Inhibition of RFC1 (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	0.0500	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149925: Binding affinity to human RFC1 incubated for 45 mins by Kinobead based pull down assay	kd	0.1323	uM

CTD chemical–gene interactions

49 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance, increases expression	3
Air Pollutants	decreases expression, increases expression, affects expression, increases abundance	3
Acetaminophen	decreases expression	2
Arsenic	affects methylation, decreases expression, increases abundance	2
Cisplatin	decreases expression, increases expression	2
Doxorubicin	decreases expression, decreases response to substance	2
Ethyl Methanesulfonate	decreases expression, increases expression	2
Methyl Methanesulfonate	decreases expression, increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
FR900359	affects phosphorylation	1
TAK-243	increases sumoylation	1
dicrotophos	decreases expression	1
lasiocarpine	decreases expression, increases metabolic processing	1
oxybenzone	increases expression	1
triphenyl phosphate	affects expression	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects expression, affects response to substance	1
tris(2-butoxyethyl) phosphate	decreases expression	1
riddelliine	decreases expression, increases metabolic processing	1
perfluorooctanoic acid	decreases expression	1
potassium chromate(VI)	increases expression	1
coumarin	decreases phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	decreases ADP-ribosylation	1
CPG-oligonucleotide	decreases expression	1
ICG 001	increases expression	1
Adenine	decreases expression	1
Ethanol	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Caffeine	decreases phosphorylation	1
Carbamazepine	affects expression	1

ChEMBL screening assays

8 unique, capped per target: 8 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652967	Binding	Binding affinity to human RFC1 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

6 cell lines: 6 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D0HT	MCRIi025-A	Induced pluripotent stem cell	Female
CVCL_D0HU	MCRIi025-B	Induced pluripotent stem cell	Female
CVCL_D0HV	MCRIi026-A	Induced pluripotent stem cell	Female
CVCL_D0HW	MCRIi026-B	Induced pluripotent stem cell	Female
CVCL_D0HX	MCRIi027-A	Induced pluripotent stem cell	Male
CVCL_D0HY	MCRIi027-B	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00455143	PHASE4	TERMINATED	Cognitive Protection - Dexmedetomidine and Cognitive Reserve
NCT00561678	PHASE4	COMPLETED	Perioperative Cognitive Function - Dexmedetomidine and Cognitive Reserve
NCT01807481	PHASE4	UNKNOWN	Phase IV Study to Evaluate the Efficacy and Safety of Mircera in PD
NCT00030979	PHASE4	COMPLETED	Donepezil to Treat Dementia in Parkinson’s Disease
NCT00043849	PHASE4	COMPLETED	Treatment of Agitation/Psychosis in Dementia/Parkinsonism (TAP/DAP)
NCT00095810	PHASE4	COMPLETED	Aripiprazole in Patients With Psychosis Associated With Parkinson’s Disease
NCT00125567	PHASE4	COMPLETED	Stalevo in Early Wearing-Off Patients
NCT00143026	PHASE4	COMPLETED	Study to Compare the Effect of Treatment With Carbidopa/Levodopa/Entacapone on the Quality of Life of Patients With Parkinson’s Disease. This Study is Not Recruiting in the United States
NCT00144300	PHASE4	COMPLETED	Ophthalmologic Safety Study of Pramipexole Immediate Release (IR) Versus Ropinirole in Early Parkinson’s Disease (PD) Patients
NCT00153972	PHASE4	COMPLETED	Dopamine Turnover Rate as Surrogate Parameter for Diagnosis of Early Parkinson’s Disease
NCT00174239	PHASE4	TERMINATED	Study Of Cabaser and Sinemet CR For The Treatment Of Nighttime Symptoms Associated With Parkinson’s Disease.
NCT00215904	PHASE4	COMPLETED	D-serine Adjuvant Treatment for Parkinson’s Disease
NCT00247247	PHASE4	COMPLETED	Comtess® Versus Cabaseril® as Add-on to Levodopa in the Treatment of Parkinsonian Patients Suffering From Wearing- Off.
NCT00272688	PHASE4	COMPLETED	Continuous Delivery of Levodopa in Patients With Advanced Idiopathic Parkinsons Disease - Cost-benefit
NCT00297778	PHASE4	COMPLETED	Pramipexole Versus Placebo in Parkinson’s Disease (PD) Patients With Depressive Symptoms
NCT00304161	PHASE4	COMPLETED	Effectiveness of Antidepressant Treatment for Depression in People With Parkinson’s Disease
NCT00307450	PHASE4	COMPLETED	Efficacy and Safety of Levetiracetam Versus Placebo on Levodopa-induced Dyskinesias in Advanced Parkinson’s Disease
NCT00321854	PHASE4	COMPLETED	Study of (Mirapex) Pramipexole for the Early Treatment of Parkinsons Disease (PD)
NCT00354133	PHASE4	UNKNOWN	Controlled Trial With Deep Brain Stimulation in Patients With Early Parkinson’s Disease
NCT00373087	PHASE4	COMPLETED	COMT Polymorphism and Entacapone Efficacy
NCT00391898	PHASE4	COMPLETED	Efficacy of Levodopa/Carbidopa/Entacapone vs Levodopa/Carbidopa in Parkinson’s Disease Patients With Early Wearing-off
NCT00399477	PHASE4	COMPLETED	A Non-Blinded Study Demonstrating the Effectiveness and Safety of Azilect Alone or in Combination Therapy in Parkinson’s Disease
NCT00402233	PHASE4	COMPLETED	A Randomized, Double-blind, Active (Pramipexole 0.5 mg Tid) and Placebo Controlled, Study of Pramipexole Given 0.5 mg and 0.75 mg Bid Over 12-week Treatment in Early Parkinson’s Disease (PD) Patients
NCT00437125	PHASE4	COMPLETED	Study on the Tolerability of Duloxetine in Depressed Patients With Parkinson’s Disease
NCT00443872	PHASE4	COMPLETED	Efficacy of Orally Disintegrating Selegiline in Parkinson’s Patients Experiencing Adverse Effects With Dopamine Agonists
NCT00462007	PHASE4	COMPLETED	Study to Evaluate Initiation of Stalevo in Early Wearing-off
NCT00462254	PHASE4	TERMINATED	Ramelteon (ROZEREM) in the Treatment of Sleep Disturbances Associated With Parkinson’s Disease
NCT00477802	PHASE4	TERMINATED	Botulinum Toxin Type A (Botox) in the Management of Levodopa-Induced Peak-Dose Dyskinesias in Parkinson’s Disease
NCT00485069	PHASE4	COMPLETED	REQUIP (Ropinirole Hydrochloride) IR Long-Term Phase 4 Study
NCT00489255	PHASE4	COMPLETED	Safety/Efficacy of Tigan® to Control Nausea/Vomiting Experienced During Apokyn® Initiation and Treatment
NCT00526630	PHASE4	COMPLETED	Methylphenidate for the Treatment of Gait Impairment in Parkinson’s Disease
NCT00571285	PHASE4	TERMINATED	Clinical Effects of Vitamin D Repletion in Patients With Parkinson’s Disease
NCT00584025	PHASE4	WITHDRAWN	Keppra IV for the Treatment of Motor Fluctuations in Parkinson’s Disease
NCT00584090	PHASE4	WITHDRAWN	Solifenacin Succinate (VESIcare) for the Treatment of Urinary Incontinence in Parkinson’s Disease
NCT00590122	PHASE4	COMPLETED	Parcopa Versus Carbidopa-levodopa in a Single Dose Cross-over Comparison Study
NCT00594464	PHASE4	COMPLETED	A Trial of Neupro® (Rotigotine Transdermal Patch) in Patients With Parkinson’s Disease Undergoing Surgery
NCT00601978	PHASE4	WITHDRAWN	Carbidopa/Levodopa Versus Carbidopa/Levodopa/Entacapone on Markers of Event Related Potentials (ERPs) in Patients With Idiopathic Parkinson’s Disease (PD) and End-of-dose Wearing Off
NCT00632762	PHASE4	COMPLETED	Long-Term Effects of Amantadine in Parkinsonian (AMANDYSK)
NCT00640159	PHASE4	COMPLETED	Selegiline to Zelapar Switch Study in Parkinson Disease Patients
NCT00642356	PHASE4	TERMINATED	Carbidopa/Levodopa/Entacapone Versus Immediate Release (IR) Carbidopa/Levodopa on Non-motor Symptoms in Patients With Idiopathic Parkinson’s Disease and Demonstrating Non-motor Symptoms of Wearing Off