RUBCN

Summary

RUBCN (rubicon autophagy regulator, HGNC:28991) is a protein-coding gene on chromosome 3q29, encoding Run domain Beclin-1-interacting and cysteine-rich domain-containing protein (Q92622). Inhibits PIK3C3 activity; under basal conditions negatively regulates PI3K complex II (PI3KC3-C2) function in autophagy.

The protein encoded by this gene is a negative regulator of autophagy and endocytic trafficking and controls endosome maturation. This protein contains two conserved domains, an N-terminal RUN domain and a C-terminal DUF4206 domain. The RUN domain is involved in Ras-like GTPase signaling, and the DUF4206 domain contains a diacylglycerol (DAG) binding-like motif. Mutation in this gene results in deletion of the DAG binding-like motif and causes a recessive ataxia. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene.

Source: NCBI Gene 9711 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal recessive spinocerebellar ataxia 15 (Strong, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 272 total — 2 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 24
• MANE Select transcript: NM_014687

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28991
Approved symbol	RUBCN
Name	rubicon autophagy regulator
Location	3q29
Locus type	gene with protein product
Status	Approved
Aliases	rubicon, rundataxin
Ensembl gene	ENSG00000145016
Ensembl biotype	protein_coding
OMIM	613516
Entrez	9711

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 10 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000273582, ENST00000296343, ENST00000413360, ENST00000415452, ENST00000447048, ENST00000449205, ENST00000467303, ENST00000471364, ENST00000472149, ENST00000474214, ENST00000707076, ENST00000854678, ENST00000935231

RefSeq mRNA: 3 — MANE Select: NM_014687 NM_001145642, NM_001346873, NM_014687

CCDS: CCDS43195, CCDS46987

Canonical transcript exons

ENST00000296343 — 20 exons

Exon	Start	End
ENSE00001057199	197696954	197697049
ENSE00001057213	197701708	197701864
ENSE00001057219	197695866	197695981
ENSE00001057225	197694375	197694585
ENSE00001080159	197700613	197701146
ENSE00001606576	197682470	197682615
ENSE00001614306	197676885	197677038
ENSE00001630213	197668867	197675196
ENSE00001657659	197677480	197677541
ENSE00001675235	197675422	197675515
ENSE00001748293	197681129	197681367
ENSE00001762455	197736655	197736904
ENSE00001765006	197693715	197693816
ENSE00001787440	197681835	197681899
ENSE00003504939	197717977	197718130
ENSE00003517503	197705092	197705175
ENSE00003549433	197684157	197684217
ENSE00003579775	197703548	197703654
ENSE00003650474	197683307	197683439
ENSE00003680526	197704542	197704701

Expression profiles

Bgee: expression breadth ubiquitous, 285 present calls, max score 94.14.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.7314 / max 299.2362, expressed in 1792 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
46451	14.9692	1785
46455	1.1350	435
46453	0.5818	123
46456	0.4706	222
46452	0.2503	91
46454	0.2238	108
46457	0.1007	36

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	94.14	gold quality
postcentral gyrus	UBERON:0002581	91.55	gold quality
middle frontal gyrus	UBERON:0002702	91.22	gold quality
paraflocculus	UBERON:0005351	91.13	gold quality
parietal lobe	UBERON:0001872	91.07	gold quality
frontal pole	UBERON:0002795	90.50	gold quality
CA1 field of hippocampus	UBERON:0003881	90.19	gold quality
endometrium epithelium	UBERON:0004811	90.00	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	89.64	gold quality
orbitofrontal cortex	UBERON:0004167	89.53	gold quality
superior frontal gyrus	UBERON:0002661	89.50	gold quality
cerebellum	UBERON:0002037	89.28	gold quality
cerebellar cortex	UBERON:0002129	89.25	gold quality
cerebellar hemisphere	UBERON:0002245	89.24	gold quality
entorhinal cortex	UBERON:0002728	89.19	gold quality
buccal mucosa cell	CL:0002336	89.14	gold quality
granulocyte	CL:0000094	88.70	gold quality
right hemisphere of cerebellum	UBERON:0014890	88.43	gold quality
bone marrow cell	CL:0002092	88.42	gold quality
medulla oblongata	UBERON:0001896	88.37	gold quality
superior vestibular nucleus	UBERON:0007227	88.26	gold quality
endothelial cell	CL:0000115	88.14	silver quality
ventral tegmental area	UBERON:0002691	88.13	gold quality
apex of heart	UBERON:0002098	87.73	gold quality
blood	UBERON:0000178	87.71	gold quality
cerebellar vermis	UBERON:0004720	87.60	gold quality
lateral globus pallidus	UBERON:0002476	87.36	gold quality
cortical plate	UBERON:0005343	87.31	gold quality
monocyte	CL:0000576	87.30	gold quality
leukocyte	CL:0000738	87.27	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-8142	yes	23.38
E-ANND-3	yes	13.92
E-MTAB-6678	yes	4.64

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

135 targeting RUBCN, 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-8485	100.00	77.57	4731
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-767-5P	99.95	70.85	993
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-302A-3P	99.89	71.23	1777
HSA-MIR-302B-3P	99.89	71.23	1777
HSA-MIR-302C-3P	99.89	71.20	1778
HSA-MIR-302D-3P	99.89	71.25	1777
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-93-5P	99.88	73.98	2606
HSA-MIR-7845-5P	99.88	64.88	771
HSA-MIR-3919	99.87	69.45	2489

Literature-anchored findings (GeneRIF, showing 19)

• Two Beclin 1 associated proteins, Atg14L and Rubicon, were identified. (PMID:19270696)
• we report the identification of a family with three children affected with a new form of recessive ataxia, which we suggest naming ‘Salih ataxia’, and of a frameshift mutation of KIAA0226 (rundataxin) that segregates with the disease (PMID:20826435)
• Rubicon and PLEKHM1 specifically and directly interact with Rab7 via their RH domain; this interaction is critical for their function; show Rubicon but not PLEKHM1 uniquely regulates membrane trafficking via simultaneously binding both Rab7 and PI3-kinase (PMID:20943950)
• Rubicon serves as a previously unknown Rab7 effector to ensure the proper progression of the endocytic pathway. (PMID:20974968)
• a critical role of the Rubicon RUN domain in PI3KC3 and autophagy regulation (PMID:21062745)
• Rubicon may thus be pivotal to generating an optimal intracellular immune response against microbial infection. (PMID:22423966)
• Rubicon differentially targets signaling complexes, depending on environmental stimuli, and may function to coordinate various immune responses against microbial infection. (PMID:22423967)
• New DNA sequencing technologies are enabling us to investigate the whole or large targeted proportions of the genome in a rapid, affordable, and comprehensive way. Exome and targeted sequencing rundataxin genes causing ataxia. (PMID:22527681)
• This study demonistrated that KIAA0226 mutation impairs Rubicon endosomal localization (PMID:23728897)
• HCV, by differentially inducing the expression of Rubicon and UVRAG, temporally regulated the autophagic flux to enhance its replication. (PMID:25807108)
• Rubicon thus functions as an important negative regulator of the innate immune response, enhances viral replication and may play a role in viral immune evasion. (PMID:28392573)
• Rubicon (Rubcn) was identified as a negative regulator of canonical autophagy and endosomal trafficking [Review]. (PMID:29215797)
• Rubicon as a novel substrate of HUNK. (PMID:31752345)
• Identification of highly potent and selective inhibitor, TIPTP, of the p22phox-Rubicon axis as a therapeutic agent for rheumatoid arthritis. (PMID:32165681)
• Structural basis for autophagy inhibition by the human Rubicon-Rab7 complex. (PMID:32632011)
• Hepatitis C virus enhances Rubicon expression, leading to autophagy inhibition and intracellular innate immune activation. (PMID:32943718)
• Epigenome-wide three-way interaction study identifies a complex pattern between TRIM27, KIAA0226, and smoking associated with overall survival of early-stage NSCLC. (PMID:34932879)
• Neuronal Rubicon Represses Extracellular APP/Amyloid beta Deposition in Alzheimer’s Disease. (PMID:35740989)
• A RAB7A phosphoswitch coordinates Rubicon Homology protein regulation of Parkin-dependent mitophagy. (PMID:38728007)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	Rubcn	ENSMUSG00000035629
rattus_norvegicus	Rubcn	ENSRNOG00000059880
drosophila_melanogaster	Plekhm1	FBGN0034694
caenorhabditis_elegans		WBGENE00013093

Paralogs (4): RUBCNL (ENSG00000102445), DEF8 (ENSG00000140995), PLEKHM3 (ENSG00000178385), PLEKHM1 (ENSG00000225190)

Protein

Protein identifiers

Run domain Beclin-1-interacting and cysteine-rich domain-containing protein — Q92622 (reviewed: Q92622)

Alternative names: Beclin-1 associated RUN domain containing protein

All UniProt accessions (7): Q92622, A0A096LNI3, A0A9L9PY84, E9PEM3, H0Y6E6, H7C357, H7C3H3

UniProt curated annotations — full annotation on UniProt →

Function. Inhibits PIK3C3 activity; under basal conditions negatively regulates PI3K complex II (PI3KC3-C2) function in autophagy. Negatively regulates endosome maturation and degradative endocytic trafficking and impairs autophagosome maturation process. Can sequester UVRAG from association with a class C Vps complex (possibly the HOPS complex) and negatively regulates Rab7 activation. Involved in regulation of pathogen-specific host defense of activated macrophages. Following bacterial infection promotes NADH oxidase activity by association with CYBA thereby affecting TLR2 signaling and probably other TLR-NOX pathways. Stabilizes the CYBA:CYBB NADPH oxidase heterodimer, increases its association with TLR2 and its phagosome trafficking to induce antimicrobial burst of ROS and production of inflammatory cytokines. Following fungal or viral infection (implicating CLEC7A (dectin-1)-mediated myeloid cell activation or RIGI-dependent sensing of RNA viruses) negatively regulates pro-inflammatory cytokine production by association with CARD9 and sequestering it from signaling complexes.

Subunit / interactions. Associates with PI3K (PI3KC3/PI3K-III/class III phosphatidylinositol 3-kinase) complex II (PI3KC3-C2) in which the core composed of the catalytic subunit PIK3C3, the regulatory subunit PIK3R4 and BECN1 is associated with UVRAG; in the complex interacts directly with PI3KC3 and UVRAG. Interacts with Rab7 (RAB7A or RAB7B) (GTP-bound form); Rab7 and UVRAG compete for RUBCN binding; can interact simultaneously with Rab7 and the PI3K complex. Interacts with CYBA and CYBB; indicative for the association with the CYBA:CYBB NADPH oxidase heterodimer. Interacts with NOX4 and probably associates with the CYBA:NOX4 complex. Interacts with YWHAB and CARD9 in a competitive and stimulation-dependent manner; RUBCN exchanges interaction from YWHAB to CARD9 upon stimulation with beta-1,3-glucan.

Subcellular location. Late endosome. Lysosome. Early endosome.

Disease relevance. Spinocerebellar ataxia, autosomal recessive, 15 (SCAR15) [MIM:615705] A form of spinocerebellar ataxia, a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCAR15 patients manifest cerebellar ataxia in early childhood and delayed motor development with delayed walking. Additional features include dysarthria, upper limb involvement, abnormal eye movements, and hyporeflexia. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (3)

UniProt ID	Names	Canonical?
Q92622-1	1	yes
Q92622-2	2
Q92622-3	3

RefSeq proteins (3): NP_001139114, NP_001333802, NP_055502* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004012	Run_dom	Domain
IPR025258	RH_dom	Domain
IPR037213	Run_dom_sf	Homologous_superfamily
IPR048569	RUBC_PIKBD	Domain
IPR052428	Autophagy_HostDef_Reg	Family

Pfam: PF02759, PF13901, PF21054

UniProt features (66 total): helix 13, region of interest 11, turn 9, modified residue 8, strand 8, compositionally biased region 5, splice variant 5, mutagenesis site 5, chain 1, domain 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
6WCW	X-RAY DIFFRACTION	2.8
9ZPD	ELECTRON MICROSCOPY	3.38

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q92622-F1	64.44	0.27

Functional residue map

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

Post-translational modifications (8): 197, 248, 266, 388, 410, 528, 562, 671

Mutagenesis-validated functional residues (5):

Position	Phenotype
248	disrupts interaction with ywhab.
912	disrupts interaction with rab7, translocation to cytoplasm; when associated with g-915, l-920 and g-923.
915	disrupts interaction with rab7, translocation to cytoplasm; when associated with g-912, l-920 and g-923.
920	disrupts interaction with rab7, translocation to cytoplasm; when associated with g-912,g-915 and g-923.
923	disrupts interaction with rab7, translocation to cytoplasm; when associated with g-912, g-915 and l-920.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 202 (showing top): BROWNE_HCMV_INFECTION_30MIN_DN, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_NEGATIVE_REGULATION_OF_ENDOCYTOSIS, DARWICHE_SKIN_TUMOR_PROMOTER_UP, DARWICHE_PAPILLOMA_RISK_LOW_UP, DARWICHE_PAPILLOMA_RISK_HIGH_UP, DARWICHE_SQUAMOUS_CELL_CARCINOMA_UP, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_MACROAUTOPHAGY, GOBP_REGULATION_OF_VESICLE_MEDIATED_TRANSPORT, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, GOBP_NEGATIVE_REGULATION_OF_AUTOPHAGY, GOBP_NEGATIVE_REGULATION_OF_TRANSPORT, GOBP_REGULATION_OF_CATABOLIC_PROCESS

GO Biological Process (9): immune system process (GO:0002376), phagocytosis (GO:0006909), autophagy (GO:0006914), negative regulation of autophagy (GO:0010507), negative regulation of endocytosis (GO:0045806), negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051898), multivesicular body sorting pathway (GO:0071985), negative regulation of autophagosome maturation (GO:1901097), endocytosis (GO:0006897)

GO Molecular Function (3): phosphatidylinositol 3-kinase inhibitor activity (GO:0141039), phosphatidylinositol phosphate binding (GO:1901981), protein binding (GO:0005515)

GO Cellular Component (6): nucleoplasm (GO:0005654), lysosome (GO:0005764), early endosome (GO:0005769), late endosome (GO:0005770), cytosol (GO:0005829), endosome (GO:0005768)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
endocytosis	2
vesicle-mediated transport	2
cellular anatomical structure	2
endosome	2
biological_process	1
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
autophagy	1
negative regulation of catabolic process	1
regulation of autophagy	1
regulation of endocytosis	1
negative regulation of transport	1
negative regulation of cellular component organization	1
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
negative regulation of intracellular signal transduction	1
negative regulation of macroautophagy	1
negative regulation of protein-containing complex disassembly	1
autophagosome maturation	1
regulation of autophagosome maturation	1
vesicle budding from membrane	1
membrane invagination	1
import into cell	1
phosphatidylinositol 3-kinase regulator activity	1
phospholipid binding	1
binding	1
nuclear lumen	1
lytic vacuole	1
cytoplasm	1
endomembrane system	1
cytoplasmic vesicle	1

Protein interactions and networks

STRING

716 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RUBCN	BECN1	Q14457	998
RUBCN	UVRAG	Q9P2Y5	998
RUBCN	PIK3C3	Q8NEB9	981
RUBCN	PIK3R4	Q99570	980
RUBCN	ATG14	Q6ZNE5	979
RUBCN	AMBRA1	Q9C0C7	829
RUBCN	ATG7	O95352	764
RUBCN	SH3GLB1	Q9Y371	761
RUBCN	RB1CC1	Q8TDY2	624
RUBCN	NRBF2	Q96F24	607
RUBCN	GRID2	O43424	603
RUBCN	ZFYVE1	Q9HBF4	594
RUBCN	LAMP1	P11279	576
RUBCN	ATG5	Q9H1Y0	576
RUBCN	CYBA	P13498	552

IntAct

102 interactions, top by confidence:

A	B	Type	Score
BECN1	ATG14	psi-mi:“MI:0914”(association)	0.980
UVRAG	BECN1	psi-mi:“MI:0914”(association)	0.970
PIK3C3	BECN1	psi-mi:“MI:0914”(association)	0.970
RUBCN	BECN1	psi-mi:“MI:0914”(association)	0.920
RUBCN	BECN1	psi-mi:“MI:0915”(physical association)	0.920
BECN1	RUBCN	psi-mi:“MI:0915”(physical association)	0.920
UVRAG	RUBCN	psi-mi:“MI:0407”(direct interaction)	0.890
RUBCN	UVRAG	psi-mi:“MI:0915”(physical association)	0.890
PIK3C3	RUBCN	psi-mi:“MI:0915”(physical association)	0.830
RUBCN	PIK3C3	psi-mi:“MI:0407”(direct interaction)	0.830
RUBCN	PIK3C3	psi-mi:“MI:0915”(physical association)	0.830
BECN1	ZWINT	psi-mi:“MI:0914”(association)	0.750
BECN1	EGFR	psi-mi:“MI:0914”(association)	0.710
EGFR	BECN1	psi-mi:“MI:0914”(association)	0.710
EGFR	RUBCN	psi-mi:“MI:0915”(physical association)	0.650
RUBCN	EGFR	psi-mi:“MI:0915”(physical association)	0.650
RUBCN	EGFR	psi-mi:“MI:2364”(proximity)	0.650
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
RUBCN	DPF2	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (107): KIAA0226 (Affinity Capture-MS), KIAA0226 (Affinity Capture-Western), KIAA0226 (Affinity Capture-Western), KIAA0226 (Affinity Capture-Western), IKBKG (Affinity Capture-Western), KIAA0226 (Co-localization), KIAA0226 (Affinity Capture-Western), BECN1 (Affinity Capture-Western), EGFR (Affinity Capture-Western), MTOR (Affinity Capture-Western), UVRAG (Affinity Capture-Western), KIAA0226 (Affinity Capture-Western), PIK3C3 (Affinity Capture-Western), KIAA0226 (Affinity Capture-RNA), KIAA0226 (Affinity Capture-MS)

ESM2 similar proteins: A0A088MLT8, A2AQ25, B3KU38, B5DF41, E9PSK7, O15079, O35274, P0DPB3, P0DPB4, P12755, P49140, P85299, Q0D2I5, Q14DQ1, Q1LY51, Q3B7M3, Q3SYW5, Q4KMA0, Q4R3X1, Q50H33, Q5F3L9, Q5FVG6, Q5RD40, Q5XKK7, Q60698, Q6ZNC4, Q6ZUS6, Q6ZWB6, Q80U23, Q80U62, Q80XA6, Q812A5, Q86YI8, Q8BXL9, Q8K2W6, Q8ND83, Q8NFH8, Q8QFX1, Q8TEK3, Q924W7

Diamond homologs: A5PJM7, A7E316, O01738, Q08AW4, Q22744, Q3TD16, Q4V8I4, Q5PQS0, Q6DDJ3, Q6DJB3, Q6ZN54, Q6ZWE6, Q7T0P6, Q7TSI1, Q80U62, Q8BM47, Q92622, Q99J78, Q9H714, Q9VTT9, Q9Y4G2, Q08DX0, Q8BIJ7, Q8IWE5, Q8TEQ0, Q96T51, Q9D3S3, P34125, P09215, P28867, Q05655, Q5PU49, Q9Z1S3, Q5R4V2, Q5R5R4, Q7L099, Q8WXA3

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
RUBCN	down-regulates	PIK3C3	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 42 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
Translocation of SLC2A4 (GLUT4) to the plasma membrane	5	24.9×	7e-05
SARS-CoV-2-host interactions	6	23.0×	1e-05
SARS-CoV-1 Infection	5	23.0×	8e-05
Macroautophagy	5	18.6×	2e-04
SARS-CoV-2 Infection	6	15.6×	8e-05
SARS-CoV Infections	7	12.5×	6e-05
Transcriptional Regulation by TP53	5	10.0×	2e-03
Viral Infection Pathways	8	7.9×	1e-04

GO biological processes:

GO term	Partners	Fold	FDR
cellular response to glucose starvation	5	43.2×	3e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	3
Uncertain significance	161
Likely benign	46
Benign	16

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
120216	NM_014687.4(RUBCN):c.2624del (p.Ala875fs)	Pathogenic
2775435	NM_014687.4(RUBCN):c.2647-2A>G	Pathogenic
2505356	NM_014687.4(RUBCN):c.1847+2T>G	Likely pathogenic
3220894	NM_014687.4(RUBCN):c.1553dup (p.Glu519fs)	Likely pathogenic
3380983	NM_014687.4(RUBCN):c.1358-2A>G	Likely pathogenic

SpliceAI

2906 predictions. Top by Δscore:

Variant	Effect	Δscore
3:197675511:CAGAG:C	acceptor_gain	1.0000
3:197675513:GAG:G	acceptor_gain	1.0000
3:197675513:GAGC:G	acceptor_loss	1.0000
3:197675514:AG:A	acceptor_gain	1.0000
3:197675515:GCTG:G	acceptor_loss	1.0000
3:197675516:C:CC	acceptor_gain	1.0000
3:197675516:CTG:C	acceptor_loss	1.0000
3:197675517:T:C	acceptor_loss	1.0000
3:197676953:T:TA	donor_gain	1.0000
3:197677473:GACTT:G	donor_loss	1.0000
3:197677474:ACTT:A	donor_loss	1.0000
3:197677476:TTAC:T	donor_loss	1.0000
3:197677477:TACTC:T	donor_loss	1.0000
3:197677478:A:AC	donor_gain	1.0000
3:197677478:ACT:A	donor_gain	1.0000
3:197677478:ACTC:A	donor_gain	1.0000
3:197677478:ACTCC:A	donor_loss	1.0000
3:197677479:C:A	donor_loss	1.0000
3:197677479:C:CA	donor_gain	1.0000
3:197677479:CT:C	donor_gain	1.0000
3:197677479:CTC:C	donor_gain	1.0000
3:197677479:CTCC:C	donor_gain	1.0000
3:197677479:CTCCT:C	donor_gain	1.0000
3:197677481:C:CA	donor_gain	1.0000
3:197677539:CAG:C	acceptor_gain	1.0000
3:197677541:GC:G	acceptor_loss	1.0000
3:197677542:C:CC	acceptor_gain	1.0000
3:197681124:CTTAC:C	donor_loss	1.0000
3:197681125:TTAC:T	donor_loss	1.0000
3:197681126:TA:T	donor_loss	1.0000

AlphaMissense

6407 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:197675490:C:T	C891Y	1.000
3:197675491:A:G	C891R	1.000
3:197675495:G:C	F889L	1.000
3:197675495:G:T	F889L	1.000
3:197675497:A:G	F889L	1.000
3:197675512:A:G	C884R	1.000
3:197681220:A:G	L780P	1.000
3:197681237:G:C	S774R	1.000
3:197681237:G:T	S774R	1.000
3:197681239:T:G	S774R	1.000
3:197681263:A:G	W766R	1.000
3:197681263:A:T	W766R	1.000
3:197681309:G:C	C750W	1.000
3:197681310:C:T	C750Y	1.000
3:197681311:A:G	C750R	1.000
3:197681318:G:C	C747W	1.000
3:197681319:C:T	C747Y	1.000
3:197681320:A:G	C747R	1.000
3:197681342:A:C	C739W	1.000
3:197681343:C:T	C739Y	1.000
3:197681344:A:G	C739R	1.000
3:197681855:C:G	C724S	1.000
3:197681855:C:T	C724Y	1.000
3:197681856:A:G	C724R	1.000
3:197681856:A:T	C724S	1.000
3:197681863:A:C	C721W	1.000
3:197681864:C:G	C721S	1.000
3:197681864:C:T	C721Y	1.000
3:197681865:A:G	C721R	1.000
3:197681865:A:T	C721S	1.000

dbSNP variants (sampled 300 via entrez): RS1000018806 (3:197686395 A>G), RS1000033572 (3:197751239 C>G,T), RS1000046794 (3:197749714 C>G,T), RS1000089038 (3:197741285 T>C), RS1000153991 (3:197684409 T>G), RS1000270848 (3:197724269 A>T), RS1000284036 (3:197715095 G>A), RS1000347039 (3:197729624 C>A,T), RS1000371025 (3:197727810 T>A,C,G), RS1000379920 (3:197709102 AATAGAT>A), RS1000399367 (3:197729927 G>A), RS1000429823 (3:197746917 G>A,C), RS1000447494 (3:197690412 T>A,C,G), RS1000541717 (3:197703182 A>T), RS1000543761 (3:197670984 C>T)

Disease associations

OMIM: gene MIM:613516 | disease phenotypes: MIM:615705, MIM:606658

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal recessive spinocerebellar ataxia 15	Strong	Autosomal recessive

Mondo (4): autosomal recessive spinocerebellar ataxia 15 (MONDO:0014311), intellectual disability (MONDO:0001071), pathologic nystagmus (MONDO:0004843), spinocerebellar ataxia type 15/16 (MONDO:0011694)

Orphanet (4): Autosomal recessive cerebellar ataxia-epilepsy-intellectual disability syndrome due to RUBCN deficiency (Orphanet:404499), Spinocerebellar ataxia type 15/16 (Orphanet:98769), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), Spinocerebellar ataxia type 16 (Orphanet:98770)

HPO phenotypes

24 total (24 of 24 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000639	Nystagmus
HP:0000750	Delayed speech and language development
HP:0001152	Saccadic smooth pursuit interruptions
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001256	Mild intellectual disability
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001265	Hyporeflexia
HP:0001270	Motor delay
HP:0001272	Cerebellar atrophy
HP:0002066	Gait ataxia
HP:0002070	Limb ataxia
HP:0002172	Postural instability
HP:0002194	Delayed gross motor development
HP:0002317	Unsteady gait
HP:0002395	Lower limb hyperreflexia
HP:0002600	Hyporeflexia of lower limbs
HP:0003593	Infantile onset
HP:0003676	Progressive
HP:0012391	Hyporeflexia of upper limbs
HP:0031936	Delayed ability to walk

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST009936_11	Venous thromboembolism	9.000000e-06

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D009759	Nystagmus, Pathologic	C10.292.562.675; C11.590.400
C564685	Spinocerebellar Ataxia 15 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	3
entinostat	decreases expression, affects cotreatment	2
Ozone	affects expression, increases abundance, decreases expression	2
Cyclosporine	increases expression	2
FR900359	affects phosphorylation	1
dicrotophos	increases expression	1
beta-lapachone	decreases expression	1
sodium arsenite	increases expression	1
nickel sulfate	increases expression	1
fipronil	decreases expression, affects cotreatment	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
eprenetapopt	affects expression	1
Sunitinib	increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	affects expression, increases abundance	1
Benzo(a)pyrene	affects methylation	1
Cadmium	decreases expression, increases abundance	1
Carbamazepine	affects expression	1
DEET	decreases expression, affects cotreatment	1
Doxorubicin	decreases expression	1
Silicon Dioxide	increases expression	1
Smoke	decreases expression	1
Thiram	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Urethane	increases expression	1
Cadmium Chloride	decreases expression, increases abundance	1
Soot	decreases expression, increases abundance	1

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D5AG	HeLa S3 RUBCN KO clone 15	Cancer cell line	Female
CVCL_D5AJ	HeLa S3 RUBCN KO/HA-Parkin/HaloTag7-mGFP	Cancer cell line	Female
CVCL_D5AK	HeLa S3 RUBCN KO/HaloTag7-LC3	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability
NCT02836405	Not specified	COMPLETED	TMS for the Investigation of Brain Plasticity in Autism Spectrum Disorders