RIPOR2

Summary

RIPOR2 (RHO family interacting cell polarization regulator 2, HGNC:13872) is a protein-coding gene on chromosome 6p22.3, encoding Rho family-interacting cell polarization regulator 2 (Q9Y4F9). Acts as an inhibitor of the small GTPase RHOA and plays several roles in the regulation of myoblast and hair cell differentiation, lymphocyte T proliferation and neutrophil polarization.

This gene encodes an atypical inhibitor of the small G protein RhoA. Inhibition of RhoA activity by the encoded protein mediates myoblast fusion and polarization of T cells and neutrophils. The encoded protein is a component of hair cell stereocilia that is essential for hearing. A splice site mutation in this gene results in hearing loss in human patients.

Source: NCBI Gene 9750 — RefSeq curated summary.

At a glance

• Gene–disease (curated): nonsyndromic genetic hearing loss (Strong, ClinGen) — +4 more curated relationships
• GWAS associations: 17
• Clinical variants (ClinVar): 528 total — 1 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 15
• MANE Select transcript: NM_001286445

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13872
Approved symbol	RIPOR2
Name	RHO family interacting cell polarization regulator 2
Location	6p22.3
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0386, DIFF48, MYONAP
Ensembl gene	ENSG00000111913
Ensembl biotype	protein_coding
OMIM	611410
Entrez	9750

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 15 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000259698, ENST00000378023, ENST00000463828, ENST00000473070, ENST00000510784, ENST00000538035, ENST00000540914, ENST00000606385, ENST00000613507, ENST00000643623, ENST00000643898, ENST00000644411, ENST00000644621, ENST00000645100, ENST00000645703, ENST00000647136, ENST00000647309, ENST00000938271

RefSeq mRNA: 7 — MANE Select: NM_001286445 NM_001286445, NM_001286446, NM_001286447, NM_001346031, NM_001346032, NM_014722, NM_015864

CCDS: CCDS47383, CCDS47384, CCDS69057, CCDS69058, CCDS75410, CCDS87373

Canonical transcript exons

ENST00000643898 — 22 exons

Exon	Start	End
ENSE00000928826	24809717	24809807
ENSE00000928829	24818542	24818625
ENSE00000928830	24825226	24825428
ENSE00000928831	24828137	24828295
ENSE00000928834	24835703	24835871
ENSE00000928835	24839091	24839272
ENSE00002244369	24935838	24935960
ENSE00003462340	24830509	24830670
ENSE00003521235	24832256	24832391
ENSE00003802235	24852575	24852618
ENSE00003803611	24865301	24865450
ENSE00003803719	24860973	24861036
ENSE00003804728	24873644	24873799
ENSE00003805074	24848025	24848154
ENSE00003806170	24869094	24869147
ENSE00003807097	24849802	24849950
ENSE00003807152	24842862	24843554
ENSE00003807480	24872881	24872959
ENSE00003808079	24870866	24870889
ENSE00003808848	24875691	24875817
ENSE00003811373	24850597	24850722
ENSE00003900947	24804284	24806473

Expression profiles

Bgee: expression breadth ubiquitous, 250 present calls, max score 98.89.

FANTOM5 (CAGE): breadth broad, TPM avg 44.9047 / max 2396.9459, expressed in 886 samples.

FANTOM5 promoters (16 alternative TSS)

Promoter ID	TPM avg	Samples expressed
72232	34.8694	400
72226	3.6616	690
72231	1.9200	168
72233	0.9398	129
72251	0.7584	134
72254	0.7476	153
72253	0.5333	125
72227	0.4969	258
72224	0.4572	91
72252	0.1955	89

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
blood	UBERON:0000178	98.89	gold quality
monocyte	CL:0000576	98.88	gold quality
mononuclear cell	CL:0000842	98.85	gold quality
leukocyte	CL:0000738	98.84	gold quality
granulocyte	CL:0000094	97.95	gold quality
bronchial epithelial cell	CL:0002328	96.37	gold quality
spleen	UBERON:0002106	95.04	gold quality
vermiform appendix	UBERON:0001154	94.30	gold quality
epithelium of bronchus	UBERON:0002031	94.17	gold quality
lymph node	UBERON:0000029	94.13	gold quality
bronchus	UBERON:0002185	93.23	gold quality
bone marrow cell	CL:0002092	92.85	gold quality
epithelium of nasopharynx	UBERON:0001951	92.66	gold quality
nasopharynx	UBERON:0001728	92.65	gold quality
body of uterus	UBERON:0009853	92.48	gold quality
bone marrow	UBERON:0002371	91.51	gold quality
tonsil	UBERON:0002372	90.79	gold quality
mucosa of paranasal sinus	UBERON:0005030	89.65	gold quality
caecum	UBERON:0001153	88.79	gold quality
periodontal ligament	UBERON:0008266	88.74	gold quality
right lung	UBERON:0002167	88.56	gold quality
upper lobe of left lung	UBERON:0008952	87.45	gold quality
adenohypophysis	UBERON:0002196	86.88	gold quality
upper lobe of lung	UBERON:0008948	86.70	gold quality
myometrium	UBERON:0001296	86.64	gold quality
pituitary gland	UBERON:0000007	86.50	gold quality
gastrocnemius	UBERON:0001388	86.18	gold quality
muscle of leg	UBERON:0001383	85.94	gold quality
endocervix	UBERON:0000458	85.24	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	85.07	gold quality

Single-cell (SCXA)

Detected in 15 experiment(s), a significant marker in 10.

Experiment	Marker?	Max mean expression
E-GEOD-149689	yes	6968.92
E-ANND-2	yes	806.15
E-MTAB-11268	yes	635.94
E-MTAB-6678	yes	630.42
E-HCAD-10	yes	24.54
E-GEOD-93593	yes	23.38
E-CURD-112	yes	9.30
E-HCAD-1	yes	7.42
E-CURD-119	yes	4.80
E-MTAB-7606	no	1806.81
E-CURD-97	no	876.82
E-GEOD-106540	no	841.50
E-MTAB-2983	no	690.71
E-MTAB-7381	no	425.59
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

131 targeting RIPOR2, 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-5011-5P	100.00	83.46	5820
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-548N	99.98	71.94	4170
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-302C-5P	99.97	72.56	3642

Literature-anchored findings (GeneRIF, showing 11)

• C6ORF32 is a novel protein likely to play multiple functions, including promoting myogenic cell differentiation, cytoskeletal rearrangement and filopodia formation (PMID:17150207)
• PC3 tumors are sustained by a small number of tumor-initiating cells with stem-like characteristics, including strong self-renewal and pro-angiogenic capability and marked by the expression pattern FAM65Bhigh/MFI2low/LEF1low. (PMID:21190562)
• Fam65b expression is necessary for the complex to form. (PMID:24687993)
• show that wild-type Fam65b is expressed during embryonic and postnatal development stages in murine cochlea, and that the protein localizes to the plasma membranes of the stereocilia of inner and outer hair cells of the inner ear (PMID:24958875)
• These data together elucidate a mechanism for RHOA and pMLC polarization in stimulated neutrophils through direct inhibition of RHOA by FAM65B at the leading edge. (PMID:25588844)
• In our analyses of the DYX2 locus, we observed associations of KIAA0319, ACOT13, and FAM65B with developing cortical thickness and/or functional anisotropy. (PMID:25953057)
• Mouse Ripor2 forms ring-like structures at the base of stereocilia and interacts with RhoC (PMID:27269051)
• FAM65B has a role in controlling proliferation of transformed and primary T cells (PMID:27556504)
• results show that Fam65b expression and phosphorylation can finely tune the amount of active RhoA in order to favor optimal T lymphocyte motility. (PMID:30254631)
• this is the first study to explore and validate the relationships between seven SNPs in the FAM65B, AGBL4, and CUX2 genes and ATDH in a Chinese population. On the basis of this case-control study, SNP rs10946737 in FAM65B may be associated with susceptibility to ATDH in Chinese Han anti-TB treatment patients. (PMID:30720667)
• RIPOR2 Expression Decreased by HPV-16 E6 and E7 Oncoproteins: An Opportunity in the Search for Prognostic Biomarkers in Cervical Cancer. (PMID:36497200)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ripor2	ENSDARG00000061752
mus_musculus	Ripor2	ENSMUSG00000036006
rattus_norvegicus	Ripor2	ENSRNOG00000018804
caenorhabditis_elegans		WBGENE00045063

Paralogs (2): RIPOR1 (ENSG00000039523), RIPOR3 (ENSG00000042062)

Protein

Protein identifiers

Rho family-interacting cell polarization regulator 2 — Q9Y4F9 (reviewed: Q9Y4F9)

All UniProt accessions (9): Q9Y4F9, A0A2R8Y4B9, A0A2R8Y4N2, A0A2R8Y7B3, A0A2R8YEE0, A0A2R8YF77, B7Z6U4, F5GX51, F5H029

UniProt curated annotations — full annotation on UniProt →

Function. Acts as an inhibitor of the small GTPase RHOA and plays several roles in the regulation of myoblast and hair cell differentiation, lymphocyte T proliferation and neutrophil polarization. Inhibits chemokine-induced T lymphocyte responses, such as cell adhesion, polarization and migration. Involved also in the regulation of neutrophil polarization, chemotaxis and adhesion. Required for normal development of inner and outer hair cell stereocilia within the cochlea of the inner ear. Plays a role for maintaining the structural organization of the basal domain of stereocilia. Involved in mechanosensory hair cell function. Required for normal hearing. Acts as an inhibitor of the small GTPase RHOA. Plays a role in fetal mononuclear myoblast differentiation by promoting filopodia and myotube formation. Maintains naive T lymphocytes in a quiescent state.

Subunit / interactions. Homooligomer; homooligomerization is regulated by RHOC and leads to the formation of concatemers through the association of N- and C-termini. Interacts with 14-3-3 proteins; these interactions occur during myogenic cell differentiation. Interacts with HDAC6; this interaction occurs during early myogenic differentiation and prevents HDAC6 to deacetylate tubulin. Interacts with DYSF; this interaction occurs during early myogenic differentiation. Interacts with MYOF. Interacts with RHOC. Isoform 1 and isoform 2 interact (via active GTP- or inactive GDP-bound forms) with RHOA; these interactions are direct, block the loading of GTP to RHOA and decrease upon chemokine CCL19 stimulation in primary T lymphocytes. Isoform 2 interacts (phosphorylated form) with HDAC6; this interaction induces T cell proliferation arrest. Isoform 2 interacts (phosphorylated form) with 14-3-3 proteins; these interactions induces T cell proliferation arrest. Isoform 2 interacts with 14-3-3 proteins. Isoform 2 interacts (via phosphorylated form) with YWHAB; this interaction occurs in a chemokine-dependent manner and does not compete for binding of RIPOR2 with RHOA nor blocks inhibition of RIPOR2-mediated RHOA activity. Isoform 2 interacts with YWHAE. Isoform 2 interacts with YWHAQ.

Subcellular location. Cytoplasm. Cytoskeleton. Cell projection. Filopodium. Stereocilium. Stereocilium membrane. Apical cell membrane Cytoplasm Cytoplasm.

Tissue specificity. Expressed in primary fetal mononuclear myoblast. Expressed strongly in naive T lymphocytes. Expressed weakly in activated T lymphocytes (at protein level). Expressed in blood cells and adult tissues of hematopoietic origin, such as the secondary lymphoid organs. Expressed in cytotrophoblast.

Post-translational modifications. Phosphorylated. Isoform 2 is phosphorylated in T cells. Chemokine-induced phosphorylation of isoform 2 in neutrophils occurs in a PKC- and AKT-dependent manner, resulting in RIPOR2 interaction with YWHAB and stabilization. Isoform 2 is phosphorylated by PKCA, AKT1 and MAPKAPK1A; in vitro. Acetylated during myogenic differentiation.

Disease relevance. Deafness, autosomal recessive, 104 (DFNB104) [MIM:616515] A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. The disease is caused by variants affecting the gene represented in this entry. Deafness, autosomal dominant, 21 (DFNA21) [MIM:607017] A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. DFNA21 is an autosomal dominant, progressive form with incomplete penetrance. Age at onset ranges from infancy to late adulthood. The disease is caused by variants affecting the gene represented in this entry.

Induction. Up-regulated during fetal mononuclear myoblast differentiation. Up-regulated during cytotrophoblast differentiation. Up-regulated during granulocyte differentiation. Isoform 1 and isoform 2 are down-regulated in T lymphocytes upon T-cell antigen receptor (TCR) stimulation. Isoform 1 and isoform 2 are up-regulated by FOXO1.

Miscellaneous. Cells lacking isoform 2 exhibit a severe reduction of myotube formation. In contrast, isoform 2 overexpression induces formation of filopodia.

Similarity. Belongs to the RIPOR family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9Y4F9-1	1	yes
Q9Y4F9-2	2, PL48

RefSeq proteins (7): NP_001273374, NP_001273375, NP_001273376, NP_001332960, NP_001332961, NP_055537, NP_056948 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011989	ARM-like	Homologous_superfamily
IPR016024	ARM-type_fold	Homologous_superfamily
IPR026136	RIPOR3	Family
IPR031780	FAM65_N	Domain

Pfam: PF15903

UniProt features (34 total): sequence variant 8, mutagenesis site 7, modified residue 6, region of interest 3, splice variant 3, compositionally biased region 3, coiled-coil region 2, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y4F9-F1	66.28	0.31

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 (6): 37, 341, 523, 573, 585, 21

Mutagenesis-validated functional residues (7):

Position	Phenotype
21	reduces phosphorylation, interaction with hdac6, ywhab and 14-3-3 proteins, localization at the front of the neutrophil
37	reduces phosphorylation, interaction with hdac6, ywhab and 14-3-3 proteins, localization at the front of the neutrophil
151–152	inhibits interaction with rhoa and does not prevent t cell proliferation inhibition; in isoform 2.
155–156	inhibits interaction with rhoa; in isoform 2.
341	reduces phosphorylation, interaction with hdac6, ywhab and 14-3-3 proteins, localization at the front of the neutrophil
523	reduces phosphorylation, interaction with hdac6, ywhab and 14-3-3 proteins, localization at the front of the neutrophil
585	reduces phosphorylation, interaction with hdac6, ywhab and 14-3-3 proteins, localization at the front of the neutrophil

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-9662360	Sensory processing of sound by inner hair cells of the cochlea
R-HSA-9662361	Sensory processing of sound by outer hair cells of the cochlea

MSigDB gene sets: 508 (showing top): BROWNE_HCMV_INFECTION_30MIN_DN, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_CHROMOSOME_ORGANIZATION, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, GOBP_MYELOID_LEUKOCYTE_MIGRATION, GOBP_CELL_CHEMOTAXIS, BASSO_B_LYMPHOCYTE_NETWORK, GOBP_RESPONSE_TO_PEPTIDE, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, GOBP_NEGATIVE_REGULATION_OF_LEUKOCYTE_PROLIFERATION, CHUNG_BLISTER_CYTOTOXICITY_DN, GOBP_POSITIVE_REGULATION_OF_CELLULAR_EXTRAVASATION, GOBP_STRIATED_MUSCLE_CELL_DIFFERENTIATION

GO Biological Process (26): chemotaxis (GO:0006935), cell adhesion (GO:0007155), negative regulation of cell adhesion (GO:0007162), muscle organ development (GO:0007517), sensory perception of sound (GO:0007605), cell differentiation (GO:0030154), negative regulation of Rho protein signal transduction (GO:0035024), negative regulation of T cell proliferation (GO:0042130), positive regulation of myoblast differentiation (GO:0045663), positive regulation of filopodium assembly (GO:0051491), regulation of cell cycle (GO:0051726), positive regulation of neutrophil chemotaxis (GO:0090023), regulation of mitotic spindle assembly (GO:1901673), positive regulation of myoblast fusion (GO:1901741), negative regulation of establishment of T cell polarity (GO:1903904), negative regulation of protein localization to cell leading edge (GO:1905872), cellular response to chemokine (GO:1990869), regulation of establishment of cell polarity (GO:2000114), positive regulation of neutrophil extravasation (GO:2000391), negative regulation of T cell migration (GO:2000405), negative regulation of Rho guanyl-nucleotide exchange factor activity (GO:2001107), negative regulation of signal transduction (GO:0009968), establishment of protein localization (GO:0045184), protein homooligomerization (GO:0051260), auditory receptor cell stereocilium organization (GO:0060088), cellular response to mechanical stimulus (GO:0071260)

GO Molecular Function (3): 14-3-3 protein binding (GO:0071889), protein binding (GO:0005515), identical protein binding (GO:0042802)

GO Cellular Component (11): cytoplasm (GO:0005737), cytosol (GO:0005829), cytoskeleton (GO:0005856), apical plasma membrane (GO:0016324), filopodium (GO:0030175), stereocilium (GO:0032420), stereocilium membrane (GO:0060171), plasma membrane (GO:0005886), membrane (GO:0016020), cell projection (GO:0042995), actin-based cell projection (GO:0098858)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Sensory processing of sound	2

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
negative regulation of T cell activation	2
positive regulation of neutrophil migration	2
protein binding	2
actin-based cell projection	2
response to chemical	1
taxis	1
cellular process	1
cell adhesion	1
regulation of cell adhesion	1
negative regulation of cellular process	1
animal organ development	1
muscle structure development	1
sensory perception of mechanical stimulus	1
cellular developmental process	1
Rho protein signal transduction	1
regulation of Rho protein signal transduction	1
negative regulation of small GTPase mediated signal transduction	1
T cell proliferation	1
regulation of T cell proliferation	1
negative regulation of lymphocyte proliferation	1
myoblast differentiation	1
positive regulation of cell differentiation	1
regulation of myoblast differentiation	1
filopodium assembly	1
regulation of filopodium assembly	1
positive regulation of plasma membrane bounded cell projection assembly	1
cell cycle	1
regulation of cellular process	1
neutrophil chemotaxis	1
positive regulation of granulocyte chemotaxis	1
regulation of neutrophil chemotaxis	1
regulation of mitotic spindle organization	1
regulation of spindle assembly	1
mitotic spindle assembly	1
myoblast fusion	1
positive regulation of syncytium formation by plasma membrane fusion	1
regulation of myoblast fusion	1
establishment of T cell polarity	1
regulation of establishment of T cell polarity	1

Protein interactions and networks

STRING

1648 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RIPOR2	MYOG	P15173	656
RIPOR2	RHOA	P06749	651
RIPOR2	MYOD1	P15172	575
RIPOR2	DYSF	O75923	502
RIPOR2	GRXCR2	A6NFK2	495
RIPOR2	HDAC6	Q9UBN7	459
RIPOR2	KIAA0319	Q5VV43	431
RIPOR2	C6orf62	Q9GZU0	431
RIPOR2	CEP85	Q6P2H3	421
RIPOR2	TPRN	Q4KMQ1	405
RIPOR2	ST8SIA3	O43173	404
RIPOR2	TSPAN9	O75954	403
RIPOR2	CANT1	Q8WVQ1	396
RIPOR2	HAUS1	Q96CS2	384
RIPOR2	NPEPL1	Q8NDH3	380

IntAct

18 interactions, top by confidence:

A	B	Type	Score
RHOA	RIPOR2	psi-mi:“MI:0915”(physical association)	0.670
RIPOR2	RHOA	psi-mi:“MI:0915”(physical association)	0.670
RHOC	RIPOR2	psi-mi:“MI:0915”(physical association)	0.560
RIPOR2	RHOC	psi-mi:“MI:0915”(physical association)	0.560
PER1	RIPOR2	psi-mi:“MI:0915”(physical association)	0.370
MAP2K2	RIPOR2	psi-mi:“MI:0915”(physical association)	0.370
CREB3L2	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
MTNR1B	RIPOR2	psi-mi:“MI:0915”(physical association)	0.000
RIPOR2	folC	psi-mi:“MI:0915”(physical association)	0.000
	RIPOR2	psi-mi:“MI:0915”(physical association)	0.000
rlmL	RIPOR2	psi-mi:“MI:0915”(physical association)	0.000
YWHAG	RIPOR2	psi-mi:“MI:0915”(physical association)	0.000
RIPOR2	WNK1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (22): FAM65B (Two-hybrid), FAM65B (Two-hybrid), YWHAZ (Affinity Capture-Western), FAM65B (Affinity Capture-Western), HDAC6 (Affinity Capture-Western), FAM65B (Affinity Capture-Western), DYSF (Affinity Capture-Western), FAM65B (Affinity Capture-Western), MYOF (Affinity Capture-Western), FAM65B (Two-hybrid), FAM65B (Two-hybrid), FAM65B (Two-hybrid), FAM65B (Affinity Capture-MS), FAM65B (Proximity Label-MS), FAM65B (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A0FIN4, A2VD01, A9ZLX4, D2HNW6, D4A7U2, O88974, O94988, P10914, P14316, P15314, P16236, P17433, P17947, P23570, P23906, P49140, Q00IB7, Q13506, Q13905, Q15047, Q1LY51, Q3B7M3, Q3SZP0, Q3TTA7, Q3UWM4, Q4V7W5, Q5HYC2, Q5RJA1, Q5XJV7, Q61122, Q62722, Q6A098, Q6AI12, Q6BDS1, Q6DFR2, Q6GQL0, Q6PKU1, Q6ZMT4, Q6ZNC4, Q80TJ7

Diamond homologs: A1L3T7, A9ZLX4, Q1LU99, Q3B7M3, Q4FZU8, Q5EB20, Q5F3L9, Q68FE6, Q6ZS17, Q7TP54, Q80U16, Q96MK2, Q9Y4F9, O46119, O46414, O46415, O65100, P02791, P02792, P02793, P02794, P07229, P07797, P07798, P08267, P09451, P09528, P0C7X4, P17663, P18685, P18686, P19130, P19132, P19133, P19975, P19976, P25319, P25320, P25699, P25915

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	242
Likely benign	132
Benign	117

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
208145	NM_001286445.3(RIPOR2):c.189-1G>A	Pathogenic
2498247	NM_001286445.3(RIPOR2):c.1498C>T (p.Arg500Ter)	Likely pathogenic

SpliceAI

3745 predictions. Top by Δscore:

Variant	Effect	Δscore
6:24806392:T:TA	donor_gain	1.0000
6:24809709:AAACT:A	donor_loss	1.0000
6:24809710:AACTC:A	donor_loss	1.0000
6:24809711:ACTCA:A	donor_loss	1.0000
6:24809712:CTCAC:C	donor_loss	1.0000
6:24809713:TCACC:T	donor_loss	1.0000
6:24809714:CACC:C	donor_loss	1.0000
6:24809714:CACCC:C	donor_loss	1.0000
6:24809715:A:C	donor_loss	1.0000
6:24809715:AC:A	donor_gain	1.0000
6:24809715:ACCCA:A	donor_loss	1.0000
6:24809716:C:A	donor_loss	1.0000
6:24809716:CC:C	donor_gain	1.0000
6:24818488:G:C	donor_gain	1.0000
6:24818492:AG:A	donor_gain	1.0000
6:24825220:TCTTA:T	donor_loss	1.0000
6:24825221:CTTAC:C	donor_loss	1.0000
6:24825222:TTACC:T	donor_loss	1.0000
6:24825223:TACCT:T	donor_loss	1.0000
6:24825224:A:AT	donor_loss	1.0000
6:24825225:C:A	donor_loss	1.0000
6:24825424:GGAAA:G	acceptor_gain	1.0000
6:24825425:GAAA:G	acceptor_gain	1.0000
6:24825427:AA:A	acceptor_gain	1.0000
6:24825428:AC:A	acceptor_loss	1.0000
6:24825429:C:CC	acceptor_gain	1.0000
6:24827206:T:TA	donor_gain	1.0000
6:24828134:CACCT:C	donor_loss	1.0000
6:24828135:A:AT	donor_loss	1.0000
6:24828136:C:A	donor_loss	1.0000

AlphaMissense

6879 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:24849823:A:G	L309P	1.000
6:24839193:A:G	L667P	0.999
6:24839195:G:C	F666L	0.999
6:24839195:G:T	F666L	0.999
6:24839197:A:G	F666L	0.999
6:24839201:A:C	F664L	0.999
6:24839201:A:T	F664L	0.999
6:24839203:A:G	F664L	0.999
6:24839211:A:G	L661S	0.999
6:24849806:A:G	W315R	0.999
6:24849806:A:T	W315R	0.999
6:24849817:A:G	L311P	0.999
6:24849853:A:T	V299D	0.999
6:24850653:A:G	W248R	0.999
6:24850653:A:T	W248R	0.999
6:24850683:C:G	G238R	0.999
6:24850695:A:G	W234R	0.999
6:24850695:A:T	W234R	0.999
6:24852605:A:C	F214L	0.999
6:24852605:A:T	F214L	0.999
6:24852607:A:G	F214L	0.999
6:24875726:A:C	F22L	0.999
6:24875726:A:T	F22L	0.999
6:24875728:A:G	F22L	0.999
6:24835728:A:G	L749P	0.998
6:24839193:A:T	L667Q	0.998
6:24839196:A:C	F666C	0.998
6:24839196:A:G	F666S	0.998
6:24849911:C:G	G280R	0.998
6:24850682:C:T	G238D	0.998

dbSNP variants (sampled 300 via entrez): RS1000003200 (6:25029095 T>C), RS1000036153 (6:24866414 C>A), RS1000091734 (6:24873405 T>C), RS1000092889 (6:24927825 C>A), RS1000108745 (6:25003977 G>C), RS1000110418 (6:24831435 T>C), RS1000113643 (6:24826276 A>C,T), RS1000114979 (6:24874466 A>G), RS1000116079 (6:24843706 T>C), RS1000120629 (6:25014204 T>C), RS1000150659 (6:25024512 C>G), RS1000166074 (6:25040135 T>C), RS1000181069 (6:24979300 T>G), RS1000186341 (6:24977713 T>A,C), RS1000191620 (6:24937039 C>A,T)

Disease associations

OMIM: gene MIM:611410 | disease phenotypes: MIM:607017, MIM:616515

GenCC curated gene-disease

Disease	Classification	Inheritance
nonsyndromic genetic hearing loss	Strong	Autosomal recessive
autosomal dominant nonsyndromic hearing loss 21	Moderate	Autosomal dominant
autosomal recessive nonsyndromic hearing loss 104	Moderate	Autosomal recessive
hearing loss, autosomal recessive	Supportive	Autosomal recessive
autosomal dominant nonsyndromic hearing loss	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
autosomal dominant nonsyndromic hearing loss	Limited	AD
nonsyndromic genetic hearing loss	Strong	AR

Mondo (5): autosomal dominant nonsyndromic hearing loss 21 (MONDO:0011761), autosomal recessive nonsyndromic hearing loss 104 (MONDO:0014675), nonsyndromic genetic hearing loss (MONDO:0019497), autosomal dominant nonsyndromic hearing loss (MONDO:0019587), hearing loss, autosomal recessive (MONDO:0019588)

Orphanet (3): Rare autosomal dominant non-syndromic sensorineural deafness type DFNA (Orphanet:90635), Rare autosomal recessive non-syndromic sensorineural deafness type DFNB (Orphanet:90636), Rare non-syndromic genetic deafness (Orphanet:87884)

HPO phenotypes

15 total (15 of 15 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000399	Prelingual sensorineural hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000639	Nystagmus
HP:0001263	Global developmental delay
HP:0001751	Abnormal vestibular function
HP:0002403	Positive Romberg sign
HP:0003577	Congenital onset
HP:0003596	Middle age onset
HP:0003621	Juvenile onset
HP:0003623	Neonatal onset
HP:0004463	Absent brainstem auditory responses
HP:0011462	Young adult onset
HP:0011463	Childhood onset

GWAS associations

17 associations (top):

Study	Trait	p-value
GCST001503_8	Electroencephalographic traits in alcoholism	8.000000e-06
GCST003264_822	Post bronchodilator FEV1/FVC ratio	9.000000e-07
GCST003792_1	Liver injury in anti-tuberculosis drug treatment	4.000000e-06
GCST004627_70	Lymphocyte count	2.000000e-18
GCST004632_117	Lymphocyte percentage of white cells	6.000000e-23
GCST004633_58	Neutrophil percentage of white cells	2.000000e-16
GCST010796_1137	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-12
GCST010796_1138	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-09
GCST010796_1139	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-11
GCST010796_1140	Electrocardiogram morphology (amplitude at temporal datapoints)	9.000000e-10
GCST010796_1141	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-08
GCST90002388_117	Lymphocyte count	1.000000e-32
GCST90002389_282	Lymphocyte percentage of white cells	2.000000e-46
GCST90002396_323	Mean reticulocyte volume	1.000000e-09
GCST90002398_23	Neutrophil count	2.000000e-10
GCST90002399_316	Neutrophil percentage of white cells	2.000000e-31
GCST90013406_182	Liver enzyme levels (alkaline phosphatase)	3.000000e-59

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0004800	frontal theta oscillation measurement
EFO:0004713	FEV/FVC ratio
EFO:0004587	lymphocyte count
EFO:0007993	lymphocyte percentage of leukocytes
EFO:0007990	neutrophil percentage of leukocytes
EFO:0004327	electrocardiography
EFO:0010701	mean reticulocyte volume
EFO:0004833	neutrophil count
EFO:0004533	alkaline phosphatase measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
C564634	Deafness, Autosomal Dominant 21 (supp.)
C564609	Deafness, Autosomal Recessive (supp.)
C580334	Nonsyndromic Deafness (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

2 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs10946737	Toxicity	3	Drugs For Treatment Of Tuberculosis;rifampin	Tuberculosis
rs10946739	Toxicity	3	rifampin	Tuberculosis

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs10946737	RIPOR2	3	2.25	1	Drugs For Treatment Of Tuberculosis;rifampin
rs10946739	RIPOR2	3	0.00	1	rifampin

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression	6
sodium arsenite	decreases expression, increases expression	4
bisphenol A	decreases expression, affects expression, affects cotreatment, increases methylation	3
Nickel	decreases expression, increases expression	3
Aflatoxin B1	decreases methylation, increases expression, increases methylation	3
mercuric bromide	increases expression, affects cotreatment	2
entinostat	increases expression, affects cotreatment	2
(+)-JQ1 compound	decreases expression, increases response to substance	2
Air Pollutants	increases expression, decreases expression, increases abundance	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Smoke	increases expression, increases abundance	2
FR900359	affects phosphorylation	1
TL8-506	affects cotreatment, increases expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
lead acetate	decreases expression	1
trichostatin A	increases expression	1
methylparaben	decreases expression	1
tetrathiomolybdate	increases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Resveratrol	decreases expression	1
Temozolomide	increases expression	1
Sunitinib	decreases expression	1
Fulvestrant	increases methylation, affects cotreatment	1
Norethindrone Acetate	affects cotreatment, increases expression	1
Glyphosate	decreases expression	1
Air Pollutants, Occupational	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01802190	Not specified	TERMINATED	Prevalence of POU4F3 and SLC17A8 Mutations