RFC4

Summary

RFC4 (replication factor C subunit 4, HGNC:9972) is a protein-coding gene on chromosome 3q27.3, encoding Replication factor C subunit 4 (P35249). 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. It is a common-essential gene (DepMap: required in 95.9% of cancer cell lines).

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.

Source: NCBI Gene 5984 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Morimoto-Ryu-Malicdan neuromuscular syndrome (Strong, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 91 total — 6 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 107
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 95.9% of screened cell lines (common-essential)
• MANE Select transcript: NM_002916

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9972
Approved symbol	RFC4
Name	replication factor C subunit 4
Location	3q27.3
Locus type	gene with protein product
Status	Approved
Aliases	A1, RFC37
Ensembl gene	ENSG00000163918
Ensembl biotype	protein_coding
OMIM	102577
Entrez	5984

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 22 protein_coding, 4 retained_intron, 1 nonsense_mediated_decay

ENST00000296273, ENST00000392481, ENST00000411792, ENST00000417876, ENST00000418288, ENST00000427785, ENST00000433496, ENST00000448497, ENST00000449502, ENST00000460408, ENST00000479307, ENST00000489028, ENST00000494047, ENST00000865406, ENST00000928090, ENST00000928091, ENST00000928092, ENST00000928093, ENST00000928094, ENST00000928095, ENST00000928096, ENST00000928097, ENST00000928098, ENST00000928099, ENST00000928100, ENST00000928101, ENST00000928102

RefSeq mRNA: 2 — MANE Select: NM_002916 NM_002916, NM_181573

CCDS: CCDS3283

Canonical transcript exons

ENST00000296273 — 11 exons

Exon	Start	End
ENSE00001079639	186790326	186790406
ENSE00001079641	186790142	186790255
ENSE00001355502	186806290	186806482
ENSE00001811588	186789900	186790064
ENSE00003483193	186791725	186791850
ENSE00003497447	186794658	186794777
ENSE00003559074	186792804	186792947
ENSE00003587104	186801117	186801195
ENSE00003587140	186792490	186792610
ENSE00003625625	186797535	186797614
ENSE00003797953	186804583	186804724

Expression profiles

Bgee: expression breadth ubiquitous, 282 present calls, max score 95.29.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 19.0447 / max 484.7332, expressed in 1722 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
45983	18.6106	1721
45982	0.4342	225

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	95.29	gold quality
ganglionic eminence	UBERON:0004023	94.66	gold quality
embryo	UBERON:0000922	93.83	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	92.29	gold quality
endometrium epithelium	UBERON:0004811	90.79	gold quality
rectum	UBERON:0001052	90.74	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	90.50	gold quality
cortical plate	UBERON:0005343	90.09	gold quality
cerebellar hemisphere	UBERON:0002245	89.30	gold quality
bone marrow	UBERON:0002371	89.23	gold quality
cerebellar cortex	UBERON:0002129	89.16	gold quality
right hemisphere of cerebellum	UBERON:0014890	89.15	gold quality
mucosa of transverse colon	UBERON:0004991	88.92	gold quality
vermiform appendix	UBERON:0001154	88.38	gold quality
secondary oocyte	CL:0000655	88.28	gold quality
lymph node	UBERON:0000029	87.72	gold quality
oocyte	CL:0000023	87.39	gold quality
testis	UBERON:0000473	87.26	gold quality
cerebellum	UBERON:0002037	87.12	gold quality
granulocyte	CL:0000094	87.09	gold quality
bone marrow cell	CL:0002092	87.02	gold quality
left testis	UBERON:0004533	86.96	gold quality
trabecular bone tissue	UBERON:0002483	86.90	gold quality
right ovary	UBERON:0002118	86.85	gold quality
right testis	UBERON:0004534	86.72	gold quality
left ovary	UBERON:0002119	86.52	gold quality
body of uterus	UBERON:0009853	86.43	gold quality
ovary	UBERON:0000992	86.37	gold quality
spleen	UBERON:0002106	86.25	gold quality
body of pancreas	UBERON:0001150	86.12	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.81
E-MTAB-6379	no	1346.34
E-MTAB-6911	no	711.70
E-GEOD-110499	no	195.10
E-CURD-112	no	3.90

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F4

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 95.9% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 9)

• The knockdown of endogenous replication factor C4 decreases the growth and enhances the chemosensitivity of hepatocellular carcinoma cells. (PMID:18492021)
• RFC4 is frequently overexpressed in CRC, and is associated with tumor progression and worse survival outcome. This might be attributed to the regulation of CRC cell proliferation and cell cycle arrest by RFC4 (PMID:25407051)
• Expression level of RFC4 was up regulated in cervical squamous cell carcinoma. (PMID:28341182)
• High RFC4 levels are associated with radioresistance. (PMID:30979744)
• RFC4 promotes the progression and growth of Oral Tongue squamous cell carcinoma in vivo and vitro. (PMID:33783864)
• An RFC4/Notch1 signaling feedback loop promotes NSCLC metastasis and stemness. (PMID:33976158)
• The upregulated expression of RFC4 and GMPS mediated by DNA copy number alteration is associated with the early diagnosis and immune escape of ESCC based on a bioinformatic analysis. (PMID:34520390)
• Sequential gene expression analysis of cervical malignant transformation identifies RFC4 as a novel diagnostic and prognostic biomarker. (PMID:36352434)
• Knockdown of RFC4 inhibits the cell proliferation of nasopharyngeal carcinoma in vitro and in vivo. (PMID:36562948)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	rfc4	ENSDARG00000042458
mus_musculus	Rfc4	ENSMUSG00000022881
rattus_norvegicus	Rfc4	ENSRNOG00000001816
drosophila_melanogaster	CG8142	FBGN0030871
caenorhabditis_elegans		WBGENE00004340

Paralogs (3): RFC2 (ENSG00000049541), RFC5 (ENSG00000111445), RFC3 (ENSG00000133119)

Protein

Protein identifiers

Replication factor C subunit 4 — P35249 (reviewed: P35249)

Alternative names: Activator 1 37 kDa subunit, Activator 1 subunit 4, Replication factor C 37 kDa subunit

All UniProt accessions (8): C9J8M3, C9JGY5, C9JW34, C9JXZ7, C9JZI1, P35249, F8WE44, H7C1P0

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. The RFC4 subunit probably functions as a scaffold on which the other complex components can assemble.

Subunit / interactions. Subunit of the RFC complex, an heteropentameric complex consisting of a large subunit RFC1 and four small subunits RFC2, RFC3, RFC4 and RFC5; the RFC complex interacts with PCNA. Forms an heterotetrameric complex with RFC2, RFC3 and RFC5; this complex has ATPase activity but is not stimulated by PCNA. The heterotetramer of subunits RFC2, RFC3, RFC4 and RFC5 interacts with RAD17. Interacts with ATAD5. Interacts with CTF18. Interacts with CNTD1; this interaction facilitates crossover formation.

Subcellular location. Nucleus.

Disease relevance. Morimoto-Ryu-Malicdan neuromuscular syndrome (MRMNS) [MIM:621010] An autosomal recessive neuromuscular disorder characterized by delayed gross motor development, gait disturbances, incoordination, muscle weakness, hearing impairment, and decreased body weight. Some patients are wheelchair bound and death in infancy or childhood may occur. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. Despite of the presence of a putative ATP-binding motif, this protein does not bind ATP.

Similarity. Belongs to the activator 1 small subunits family.

Isoforms (2)

UniProt ID	Names	Canonical?
P35249-1	1	yes
P35249-2	2

RefSeq proteins (2): NP_002907, NP_853551 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003593	AAA+_ATPase	Domain
IPR003959	ATPase_AAA_core	Domain
IPR008921	DNA_pol3_clamp-load_cplx_C	Homologous_superfamily
IPR013748	Rep_factorC_C	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR047854	RFC_lid	Domain
IPR050238	DNA_Rep/Repair_Clamp_Loader	Family

Pfam: PF00004, PF08542, PF21960

Enzyme classification (BRENDA):

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

UniProt features (47 total): helix 21, strand 8, sequence variant 7, turn 3, modified residue 3, splice variant 2, chain 1, region of interest 1, binding site 1

Structure

Experimental structures (PDB)

16 structures.

PDB	Method	Resolution (Å)
8UMV	ELECTRON MICROSCOPY	2.75
8UMY	ELECTRON MICROSCOPY	2.83
8UMW	ELECTRON MICROSCOPY	2.93
8ZWO	ELECTRON MICROSCOPY	2.99
8UN0	ELECTRON MICROSCOPY	3
8UII	ELECTRON MICROSCOPY	3.04
8UI8	ELECTRON MICROSCOPY	3.1
8UMU	ELECTRON MICROSCOPY	3.16
9IIN	ELECTRON MICROSCOPY	3.2
9UIQ	ELECTRON MICROSCOPY	3.2
8UMT	ELECTRON MICROSCOPY	3.33
8UNJ	ELECTRON MICROSCOPY	3.35
6VVO	ELECTRON MICROSCOPY	3.4
8UI9	ELECTRON MICROSCOPY	3.5
7Z6H	ELECTRON MICROSCOPY	3.59
8UI7	ELECTRON MICROSCOPY	4.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P35249-F1	82.68	0.43

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): 78–85

Post-translational modifications (3): 1, 6, 13

Function

Pathways and Gene Ontology

Reactome pathways

21 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-176187	Activation of ATR in response to replication stress
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-5685938	HDR through Single Strand Annealing (SSA)
R-HSA-5685942	HDR through Homologous Recombination (HRR)
R-HSA-5693607	Processing of DNA double-strand break ends
R-HSA-5693616	Presynaptic phase of homologous DNA pairing and strand exchange
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-6804756	Regulation of TP53 Activity through Phosphorylation
R-HSA-69091	Polymerase switching
R-HSA-69473	G2/M DNA damage checkpoint
R-HSA-9709570	Impaired BRCA2 binding to RAD51

MSigDB gene sets: 619 (showing top): PID_FANCONI_PATHWAY, GNF2_CKS1B, KALMA_E2F1_TARGETS, MORF_DNMT1, REACTOME_DNA_REPLICATION, MODULE_52, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, GNF2_MSH2, KANG_DOXORUBICIN_RESISTANCE_UP, MORF_ESPL1, GNF2_CENPF, GOBP_POSITIVE_REGULATION_OF_DNA_BIOSYNTHETIC_PROCESS, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, MORF_BUB1, BASSO_B_LYMPHOCYTE_NETWORK

GO Biological Process (5): DNA-templated DNA replication (GO:0006261), DNA strand elongation involved in DNA replication (GO:0006271), DNA repair (GO:0006281), positive regulation of DNA-directed DNA polymerase activity (GO:1900264), DNA replication (GO:0006260)

GO Molecular Function (8): DNA binding (GO:0003677), ATP binding (GO:0005524), ATP hydrolysis activity (GO:0016887), enzyme binding (GO:0019899), nucleotide binding (GO:0000166), DNA clamp loader activity (GO:0003689), protein binding (GO:0005515), single-stranded DNA helicase activity (GO:0017116)

GO Cellular Component (6): nucleus (GO:0005634), nucleoplasm (GO:0005654), DNA replication factor C complex (GO:0005663), Ctf18 RFC-like complex (GO:0031390), Elg1 RFC-like complex (GO:0031391), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-12 pathways:

Category	Pathways
Translesion synthesis by Y family DNA polymerases bypasses lesions on DNA template	5
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	3
G2/M Checkpoints	2
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
Homologous DNA Pairing and Strand Exchange	1
Regulation of TP53 Activity	1
Leading Strand Synthesis	1
Lagging Strand Synthesis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA replication	2
DNA metabolic process	2
chromosome	2
DNA-templated DNA replication	1
DNA strand elongation	1
DNA synthesis involved in DNA replication	1
DNA damage response	1
DNA-directed DNA polymerase activity	1
positive regulation of catalytic activity	1
regulation of transferase activity	1
positive regulation of DNA biosynthetic process	1
DNA biosynthetic process	1
nucleic acid binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
ribonucleoside triphosphate phosphatase activity	1
ATP-dependent activity	1
protein binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
DNA binding	1
ATP-dependent activity, acting on DNA	1
binding	1
DNA helicase activity	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular anatomical structure	1
replication fork	1
protein-containing complex	1
nuclear protein-containing complex	1
catalytic complex	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

3376 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RFC4	RFC3	P40938	991
RFC4	RFC2	P32846	990
RFC4	RFC5	P40937	989
RFC4	CHTF18	Q8WVB6	931
RFC4	CHTF8	P0CG13	909
RFC4	DSCC1	Q9BVC3	906
RFC4	MSH6	P52701	894
RFC4	RFC1	P35251	874
RFC4	MSH2	P43246	863
RFC4	EXO1	Q9UQ84	831
RFC4	BRCA1	P38398	827
RFC4	MLH1	P40692	826
RFC4	NBN	O60934	815
RFC4	CHEK1	O14757	797
RFC4	FEN1	P39748	796

IntAct

182 interactions, top by confidence:

A	B	Type	Score
RFC5	RFC4	psi-mi:“MI:0915”(physical association)	0.950
RFC4	RFC5	psi-mi:“MI:0915”(physical association)	0.950
RFC4	RFC5	psi-mi:“MI:0914”(association)	0.950
RFC3	RFC4	psi-mi:“MI:0915”(physical association)	0.860
RFC4	RFC3	psi-mi:“MI:0915”(physical association)	0.860
HUS1	RAD1	psi-mi:“MI:0914”(association)	0.840
RFC4	RFC2	psi-mi:“MI:0914”(association)	0.810
RFC2	RFC4	psi-mi:“MI:0915”(physical association)	0.810
RFC4	RFC2	psi-mi:“MI:0915”(physical association)	0.810
RFC4	RNF41	psi-mi:“MI:0915”(physical association)	0.780
RNF41	RFC4	psi-mi:“MI:0915”(physical association)	0.780
RAD17	RFC4	psi-mi:“MI:0914”(association)	0.730
RFC5	RAD17	psi-mi:“MI:0914”(association)	0.730

BioGRID (357): RFC5 (Two-hybrid), RNF41 (Two-hybrid), RFC4 (Affinity Capture-MS), RFC4 (Affinity Capture-MS), RFC4 (Affinity Capture-MS), RFC4 (Affinity Capture-MS), RFC4 (Affinity Capture-MS), RFC4 (Affinity Capture-MS), RFC5 (Two-hybrid), RFC2 (Co-fractionation), RFC4 (Co-fractionation), RFC4 (Co-fractionation), RFC5 (Co-fractionation), TRIM33 (Co-fractionation), RFC4 (Affinity Capture-MS)

ESM2 similar proteins: A0JN39, A1C4A5, A1DBH2, A2R5J1, B0Y9Q4, D2SW95, F1QGH9, O13396, O24617, P21271, P23514, P33121, P35249, P43246, P43247, P46735, P53041, P53042, P53618, P54275, P70569, Q00647, Q05096, Q06364, Q0CEX5, Q0DBU5, Q13616, Q1DLP2, Q2U919, Q2US45, Q3MHE4, Q4WC55, Q5R4A0, Q5R4G6, Q5R922, Q5XXB5, Q5ZIA5, Q60676, Q66HV4, Q7ZVX6

Diamond homologs: A0B6D7, A1RSA2, A1RV38, A1RWU7, A2SQR6, A2SQT3, A3CTR4, A3CUX9, A3DNV9, A3MS28, A4FZ74, A4WGV2, A4WLY0, A5UMF3, A5UMF4, A6US36, A6VJ61, A7I781, A7I8Y0, A9A6K6, B0R601, B0R7H7, O14003, O26342, O26343, O28219, O29072, O57852, O57853, O74111, O94449, O94697, P0C7N7, P34429, P35249, P35250, P38629, P40339, P40348, P40937

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
RFC4	“form complex”	“RF-C complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 153 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	7	46.7×	1e-08
Translesion synthesis by POLI	7	44.0×	1e-08
Translesion synthesis by POLK	7	41.5×	1e-08
Translesion Synthesis by POLH	7	39.3×	2e-08
PCNA-Dependent Long Patch Base Excision Repair	7	34.0×	5e-08
Gap-filling DNA repair synthesis and ligation in GG-NER	8	32.8×	1e-08
Polymerase switching on the C-strand of the telomere	8	31.6×	1e-08
Recognition of DNA damage by PCNA-containing replication complex	8	28.5×	2e-08

GO biological processes:

GO term	Partners	Fold	FDR
DNA-templated DNA replication	5	20.6×	6e-04
DNA damage checkpoint signaling	6	17.3×	3e-04
ribosomal large subunit biogenesis	5	16.3×	1e-03
cellular response to ionizing radiation	5	15.1×	2e-03
cellular response to UV	6	13.0×	9e-04
cytoplasmic translation	8	10.9×	2e-04
ribosomal small subunit biogenesis	6	10.1×	2e-03
telomere maintenance	5	9.8×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	5
Uncertain significance	62
Likely benign	4
Benign	1

Top pathogenic / likely-pathogenic (11)

Variant ID	HGVS	Classification
3376523	NM_002916.5(RFC4):c.1030G>A (p.Glu344Lys)	Pathogenic
3376525	NM_002916.5(RFC4):c.1064_1065del (p.Val355fs)	Pathogenic
3376526	NM_002916.5(RFC4):c.947_950del (p.Glu316fs)	Pathogenic
3376528	NM_002916.5(RFC4):c.980_982dup (p.Ile327_Thr328insIle)	Pathogenic
3376530	NM_002916.5(RFC4):c.784del (p.Ile262fs)	Pathogenic
3376531	NM_002916.5(RFC4):c.904GCA[1] (p.Ala303del)	Pathogenic
3376524	NM_002916.5(RFC4):c.824_826del (p.Asp275del)	Likely pathogenic
3376527	NM_002916.5(RFC4):c.290+5G>T	Likely pathogenic
3773694	NM_002916.5(RFC4):c.1065_1089del (p.Met356fs)	Likely pathogenic
4532813	NM_002916.5(RFC4):c.866T>G (p.Leu289Arg)	Likely pathogenic
4532814	NM_002916.5(RFC4):c.996+4dup	Likely pathogenic

SpliceAI

1218 predictions. Top by Δscore:

Variant	Effect	Δscore
3:186791718:CTCTT:C	donor_loss	1.0000
3:186791719:TCTTA:T	donor_loss	1.0000
3:186791720:CTTA:C	donor_loss	1.0000
3:186791721:TTAC:T	donor_loss	1.0000
3:186791722:TA:T	donor_loss	1.0000
3:186791723:A:AC	donor_gain	1.0000
3:186791723:AC:A	donor_gain	1.0000
3:186791723:ACC:A	donor_gain	1.0000
3:186791724:C:CC	donor_gain	1.0000
3:186791724:CC:C	donor_gain	1.0000
3:186791724:CCC:C	donor_gain	1.0000
3:186791847:TTCC:T	acceptor_gain	1.0000
3:186791848:TCCC:T	acceptor_loss	1.0000
3:186791849:CC:C	acceptor_gain	1.0000
3:186791850:CC:C	acceptor_gain	1.0000
3:186791851:C:CC	acceptor_gain	1.0000
3:186791851:C:CG	acceptor_loss	1.0000
3:186792485:ATTAC:A	donor_loss	1.0000
3:186792486:TTACC:T	donor_loss	1.0000
3:186792487:TA:T	donor_loss	1.0000
3:186792488:A:AG	donor_loss	1.0000
3:186792489:CCTCA:C	donor_gain	1.0000
3:186792606:TTATT:T	acceptor_gain	1.0000
3:186792607:TATT:T	acceptor_gain	1.0000
3:186792608:ATT:A	acceptor_gain	1.0000
3:186792608:ATTC:A	acceptor_loss	1.0000
3:186792609:TT:T	acceptor_gain	1.0000
3:186792609:TTCT:T	acceptor_loss	1.0000
3:186792610:TCTG:T	acceptor_loss	1.0000
3:186792611:C:CC	acceptor_gain	1.0000

AlphaMissense

2346 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:186792587:C:G	R193T	1.000
3:186792815:G:C	N181K	1.000
3:186792815:G:T	N181K	1.000
3:186792818:A:C	C180W	1.000
3:186792819:C:T	C180Y	1.000
3:186792829:A:G	C177R	1.000
3:186792867:C:G	R164T	1.000
3:186792878:C:A	Q160H	1.000
3:186792878:C:G	Q160H	1.000
3:186792882:G:T	A159D	1.000
3:186792901:C:G	D153H	1.000
3:186792905:T:A	E151D	1.000
3:186792905:T:G	E151D	1.000
3:186792906:T:A	E151V	1.000
3:186792909:T:A	D150V	1.000
3:186792909:T:G	D150A	1.000
3:186792912:A:G	L149P	1.000
3:186794688:G:T	A127D	1.000
3:186794712:A:T	V119D	1.000
3:186797574:T:A	K84I	1.000
3:186797575:T:G	K84Q	1.000
3:186797577:C:T	G83E	1.000
3:186797592:C:T	G78E	1.000
3:186791810:C:A	R239I	0.999
3:186791810:C:G	R239T	0.999
3:186792568:G:C	F199L	0.999
3:186792568:G:T	F199L	0.999
3:186792569:A:G	F199S	0.999
3:186792570:A:G	F199L	0.999
3:186792583:A:C	C194W	0.999

dbSNP variants (sampled 300 via entrez): RS1000137955 (3:186800118 GCTA>G), RS1000593265 (3:186791427 G>A,T), RS1000839969 (3:186799888 A>C), RS1001190947 (3:186798150 A>G), RS1001391228 (3:186806331 G>C), RS1001622514 (3:186804027 C>CA), RS1001679678 (3:186790803 C>T), RS1001833433 (3:186798371 C>A), RS1001849892 (3:186797397 C>A), RS1002071168 (3:186803921 C>A), RS1002341772 (3:186797726 C>T), RS1002421631 (3:186804775 C>G,T), RS1002468951 (3:186793912 T>C), RS1002575351 (3:186802518 C>G), RS1002714777 (3:186791371 C>A)

Disease associations

OMIM: gene MIM:102577 | disease phenotypes: MIM:621010

GenCC curated gene-disease

Disease	Classification	Inheritance
Morimoto-Ryu-Malicdan neuromuscular syndrome	Strong	Autosomal recessive

Mondo (1): Morimoto-Ryu-Malicdan neuromuscular syndrome (MONDO:0975848)

Orphanet (0):

HPO phenotypes

107 total (30 of 107 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000365	Hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000486	Strabismus
HP:0000518	Cataract
HP:0000545	Myopia
HP:0000639	Nystagmus
HP:0000651	Diplopia
HP:0000709	Psychosis
HP:0000750	Delayed speech and language development
HP:0000763	Sensory neuropathy
HP:0000771	Gynecomastia
HP:0000821	Hypothyroidism
HP:0000822	Hypertension
HP:0000938	Osteopenia
HP:0000961	Cyanosis
HP:0001152	Saccadic smooth pursuit interruptions
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001269	Hemiparesis
HP:0001272	Cerebellar atrophy
HP:0001288	Gait disturbance
HP:0001290	Generalized hypotonia
HP:0001298	Encephalopathy
HP:0001310	Dysmetria
HP:0001324	Muscle weakness

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST001574_6	Activated partial thromboplastin time	2.000000e-203

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5725145 (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
7.44	Kd	36	nM	MOLIBRESIB
7.00	IC50	100	nM	MOLIBRESIB
5.78	Kd	1671	nM	CHEMBL5653589
5.78	ED50	1671	nM	CHEMBL5653589

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	2179094: Binding affinity against RFC4 (unknown origin) assessed as apparent dissociation constant incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	kd	0.0360	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149220: Binding affinity to human RFC4 incubated for 45 mins by Kinobead based pull down assay	kd	1.6707	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, increases expression, increases methylation	5
Cyclosporine	affects expression, decreases expression	3
Particulate Matter	decreases expression, increases abundance, affects cotreatment	3
sodium arsenite	decreases expression, increases abundance	2
cobaltous chloride	decreases expression	2
Resveratrol	affects cotreatment, increases expression, decreases expression	2
Acetaminophen	decreases expression, increases expression	2
Tetrachlorodibenzodioxin	affects expression, decreases expression	2
Valproic Acid	decreases expression, decreases methylation, increases expression	2
Aflatoxin B1	affects expression, increases expression	2
aristolochic acid I	decreases expression	1
TAK-243	increases sumoylation	1
dicrotophos	decreases expression	1
lasiocarpine	decreases expression, increases metabolic processing	1
bisphenol A	decreases expression	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects expression, affects response to substance	1
titanium dioxide	affects binding, decreases expression	1
riddelliine	decreases expression, increases metabolic processing	1
tetrahydropalmatine	increases expression	1
beta-lapachone	increases expression	1
sodium bichromate	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
nickel subsulfide	decreases expression	1
ochratoxin A	decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
beta-methylcholine	affects expression	1
2,3-dimethoxy-1,4-naphthoquinone	increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	increases reaction, affects binding	1
K 7174	decreases 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
CHEMBL5652262	Binding	Binding affinity to human RFC4 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

Clinical trials (associated diseases)

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