RIMS2

Summary

RIMS2 (regulating synaptic membrane exocytosis 2, HGNC:17283) is a protein-coding gene on chromosome 8q22.3, encoding Regulating synaptic membrane exocytosis protein 2 (Q9UQ26). Rab effector involved in exocytosis.

The protein encoded by this gene is a presynaptic protein that interacts with RAB3, a protein important for normal neurotransmitter release. The encoded protein can also bind several other synaptic proteins, including UNC-13 homolog B, ELKS/Rab6-interacting/CAST family member 1, and synaptotagmin 1. This protein is involved in synaptic membrane exocytosis. Polymorphisms in this gene have been associated with degenerative lumbar scoliosis.

Source: NCBI Gene 9699 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cone-rod synaptic disorder syndrome, congenital nonprogressive (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 7
• Clinical variants (ClinVar): 235 total — 5 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 12
• MANE Select transcript: NM_001348484

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17283
Approved symbol	RIMS2
Name	regulating synaptic membrane exocytosis 2
Location	8q22.3
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0751, RIM2, OBOE
Ensembl gene	ENSG00000176406
Ensembl biotype	protein_coding
OMIM	606630
Entrez	9699

Gene structure

Transcript identifiers

Ensembl transcripts: 31 — 24 protein_coding, 3 protein_coding_CDS_not_defined, 2 retained_intron, 2 nonsense_mediated_decay

ENST00000262231, ENST00000395361, ENST00000408894, ENST00000436393, ENST00000501515, ENST00000504942, ENST00000507677, ENST00000507740, ENST00000511046, ENST00000512598, ENST00000515551, ENST00000523362, ENST00000632716, ENST00000666250, ENST00000668113, ENST00000696799, ENST00000696800, ENST00000696801, ENST00000696802, ENST00000705941, ENST00000705942, ENST00000705943, ENST00000705944, ENST00000705945, ENST00000705946, ENST00000705947, ENST00000705948, ENST00000705949, ENST00000705950, ENST00000705951, ENST00000705952

RefSeq mRNA: 33 — MANE Select: NM_001348484 NM_001100117, NM_001282881, NM_001282882, NM_001348484, NM_001348485, NM_001348486, NM_001348487, NM_001348488, NM_001348489, NM_001348490, NM_001348491, NM_001348492, NM_001348493, NM_001348494, NM_001348495, NM_001348496, NM_001348497, NM_001348498, NM_001348499, NM_001348500, NM_001348501, NM_001348502, NM_001348503, NM_001348504, NM_001348505, NM_001348506, NM_001348507, NM_001348508, NM_001348509, NM_001395652, NM_001395653, NM_001395654, NM_014677

CCDS: CCDS43761, CCDS55269, CCDS64948, CCDS64949, CCDS94327, CCDS94328, CCDS94329, CCDS94330, CCDS94331, CCDS94332

Canonical transcript exons

ENST00000696799 — 30 exons

Exon	Start	End
ENSE00001323926	103697086	103697296
ENSE00002053937	103500610	103501062
ENSE00003545809	103766227	103766537
ENSE00003728795	103885298	103886223
ENSE00003968408	104251602	104254430
ENSE00003968412	104244916	104245057
ENSE00003968414	103716309	103716320
ENSE00003968415	104093471	104093643
ENSE00003968417	103936551	103936722
ENSE00003968418	104014506	104014615
ENSE00003968419	104251024	104251163
ENSE00003968421	103912053	103912172
ENSE00003968423	103915495	103915594
ENSE00003968424	103916414	103916537
ENSE00003968425	103921672	103921784
ENSE00003968426	103942773	103942926
ENSE00003968427	103918441	103918487
ENSE00003968428	104013442	104013621
ENSE00003968429	103910321	103910529
ENSE00003968431	103975350	103975506
ENSE00003968433	104068512	104068612
ENSE00003968434	104041326	104041358
ENSE00003968437	103652205	103652237
ENSE00003968438	103989305	103989421
ENSE00003968439	104148607	104148848
ENSE00003968440	104249487	104249588
ENSE00003968443	104248701	104248813
ENSE00003968444	103652624	103652710
ENSE00003968445	103931263	103931393
ENSE00003968446	103961065	103961133

Expression profiles

Bgee: expression breadth ubiquitous, 198 present calls, max score 96.38.

FANTOM5 (CAGE): breadth broad, TPM avg 5.6873 / max 1550.1903, expressed in 495 samples.

FANTOM5 promoters (27 alternative TSS)

Promoter ID	TPM avg	Samples expressed
90151	1.4541	106
90137	0.5920	204
90149	0.4909	88
90135	0.3226	139
90172	0.3152	127
90136	0.2926	133
90148	0.2747	72
90138	0.2370	96
90134	0.1761	74
90145	0.1666	47

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lateral nuclear group of thalamus	UBERON:0002736	96.38	gold quality
endothelial cell	CL:0000115	96.04	gold quality
middle temporal gyrus	UBERON:0002771	95.65	gold quality
Brodmann (1909) area 23	UBERON:0013554	95.60	gold quality
superior frontal gyrus	UBERON:0002661	94.90	gold quality
postcentral gyrus	UBERON:0002581	94.68	gold quality
parietal lobe	UBERON:0001872	94.47	gold quality
left adrenal gland	UBERON:0001234	94.23	gold quality
left adrenal gland cortex	UBERON:0035825	94.07	gold quality
adrenal cortex	UBERON:0001235	94.05	gold quality
right adrenal gland	UBERON:0001233	93.98	gold quality
Brodmann (1909) area 46	UBERON:0006483	93.81	gold quality
Brodmann (1909) area 10	UBERON:0013541	93.78	gold quality
primary visual cortex	UBERON:0002436	93.59	gold quality
right adrenal gland cortex	UBERON:0035827	93.55	gold quality
entorhinal cortex	UBERON:0002728	93.38	gold quality
frontal pole	UBERON:0002795	93.28	gold quality
lateral globus pallidus	UBERON:0002476	92.93	gold quality
occipital lobe	UBERON:0002021	92.77	gold quality
temporal lobe	UBERON:0001871	92.58	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	92.55	gold quality
adrenal gland	UBERON:0002369	92.40	gold quality
amygdala	UBERON:0001876	92.34	gold quality
orbitofrontal cortex	UBERON:0004167	91.91	gold quality
frontal cortex	UBERON:0001870	91.86	gold quality
putamen	UBERON:0001874	91.82	gold quality
cingulate cortex	UBERON:0003027	91.67	gold quality
anterior cingulate cortex	UBERON:0009835	91.66	gold quality
right frontal lobe	UBERON:0002810	91.48	gold quality
neocortex	UBERON:0001950	91.38	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-GEOD-137537	yes	2586.09
E-ANND-2	yes	2193.46
E-HCAD-35	yes	91.32
E-HCAD-25	yes	82.74
E-MTAB-5061	yes	13.31
E-ENAD-20	yes	8.84
E-MTAB-7316	no	3072.27
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
UNC13A	Activation

miRNA regulators (miRDB)

286 targeting RIMS2, 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-5692A	100.00	74.40	6850
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-7110-3P	100.00	73.18	2486
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-186-5P	99.99	70.83	3707
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821

Literature-anchored findings (GeneRIF, showing 6)

• Western blot analysis shows increased RIMS2 protein expression in the amygdala in schizophrenia. (PMID:18490030)
• tick-borne encephalitis virus -NS5 has high affinity to regulating synaptic membrane exocytosis-2 (RIMS2) and Scribble, whereas DENV-NS5 binds primarily to the tight junction protein zonula occludens-1 (ZO-1) (PMID:19199833)
• These data suggest that RIM2beta contributes to the stabilization of Ca(v)1.3 gating kinetics in immature cochlear inner hair cells. (PMID:20363327)
• Here, we report that, like Rab3A, RIM and Munc13 are present in human sperm and that they play a functional role in acrosomal exocytosis before the acrosomal calcium efflux (PMID:22248876)
• Electrophysiological characterization of VDCC currents revealed that the suppressive effect of RIM2alpha on voltage-dependent inactivation (VDI) was stronger than that of RIM1alpha for the CaV2.1 variant containing the region encoded by exons 44 and 47. (PMID:28377503)
• Loss of Function of RIMS2 Causes a Syndromic Congenital Cone-Rod Synaptic Disease with Neurodevelopmental and Pancreatic Involvement. (PMID:32470375)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	rims2a	ENSDARG00000101606
danio_rerio	RIMS2	ENSDARG00000113702
mus_musculus	Rims2	ENSMUSG00000037386
rattus_norvegicus	Rims2	ENSRNOG00000004201
drosophila_melanogaster	Rim	FBGN0053547
caenorhabditis_elegans		WBGENE00006750

Paralogs (4): RIMS1 (ENSG00000079841), RIMS4 (ENSG00000101098), RIMS3 (ENSG00000117016), NANOGNB (ENSG00000205857)

Protein

Protein identifiers

Regulating synaptic membrane exocytosis protein 2 — Q9UQ26 (reviewed: Q9UQ26)

Alternative names: Rab-3-interacting molecule 2, Rab-3-interacting protein 3

All UniProt accessions (24): Q9UQ26, A0A0J9YWD4, A0A0J9YXG4, A0A590UJL1, A0A590UK62, A0A8Q3SIU4, A0A8Q3SIZ1, A0A8Q3SJ08, A0A8Q3SJ53, A0A994J4Z8, A0A994J503, A0A994J586, A0A994J590, A0A994J5M2, A0A994J5M6, A0A994J7I0, A0A994J7I4, A0A994J7I6, A0A994J7W5, A0A994J7W6, D6RA03, D6RDY0, E5RI36, F8W6W8

UniProt curated annotations — full annotation on UniProt →

Function. Rab effector involved in exocytosis. May act as scaffold protein. Plays a role in dendrite formation by melanocytes.

Subunit / interactions. Interacts with RAB3A and RAB3B that have been activated by GTP-binding. Interacts with RAB3C, RAB3D and RAB26. Interacts with TSPOAP1 and RIMBP2. Interacts with PPFIA3 and PPFIA4. Interacts via its zinc finger with the first C2 domain of UNC13A. Forms a complex consisting of UNC13A, RIMS2 and RAB3A. Heterodimer with PCLO. Part of a ternary complex involving PCLO and EPAC2.

Subcellular location. Cell membrane. Synapse. Presynaptic cell membrane.

Tissue specificity. Widely expressed. Expressed in melanocytes. In fetal tissues, predominantly expressed in the brain. In the retina, expressed in the outer plexiform layer (at protein level). In the cerebellum, expressed in Purkinje cells (at protein level). In the pancreas, expressed in Langerhans islets (at protein level).

Disease relevance. Cone-rod synaptic disorder syndrome, congenital non-progressive (CRSDS) [MIM:618970] An autosomal recessive disorder characterized by reduced visual acuity, photophobia, nystagmus, distinctive electroretinographic features, neurodevelopmental delay, poor or absent language, autistic behaviors, and abnormal glucose homeostasis. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. May be due to an intron retention. May be due to an intron retention. May be due to an intron retention.

Isoforms (8)

UniProt ID	Names	Canonical?
Q9UQ26-6	6, RIM2-alpha	yes
Q9UQ26-1	1, RIM2-beta
Q9UQ26-2	2
Q9UQ26-3	3
Q9UQ26-4	4, RimL3a
Q9UQ26-5	5, RimL3c
Q9UQ26-7	7, RIM2-gamma
Q9UQ26-8	8

RefSeq proteins (33): NP_001093587, NP_001269810, NP_001269811, NP_001335413, NP_001335414, NP_001335415, NP_001335416, NP_001335417, NP_001335418, NP_001335419, NP_001335420, NP_001335421, NP_001335422, NP_001335423, NP_001335424, NP_001335425, NP_001335426, NP_001335427, NP_001335428, NP_001335429, NP_001335430, NP_001335431, NP_001335432, NP_001335433, NP_001335434, NP_001335435, NP_001335436, NP_001335437, NP_001335438, NP_001382581, NP_001382582, NP_001382583, NP_055492 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000008	C2_dom	Domain
IPR001478	PDZ	Domain
IPR010911	Rab_BD	Domain
IPR011011	Znf_FYVE_PHD	Homologous_superfamily
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR017455	Znf_FYVE-rel	Domain
IPR035892	C2_domain_sf	Homologous_superfamily
IPR036034	PDZ_sf	Homologous_superfamily
IPR039032	Rim-like	Family
IPR054386	RIM_Znf	Domain

Pfam: PF00168, PF00595, PF22601

UniProt features (87 total): compositionally biased region 17, strand 16, splice variant 14, binding site 8, modified residue 7, region of interest 6, domain 4, sequence variant 4, helix 4, sequence conflict 3, turn 2, chain 1, zinc finger region 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
1V27	SOLUTION NMR
1WFG	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UQ26-F1	54.83	0.18

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 (8): 123; 126; 139; 142; 147; 150; 165; 168

Post-translational modifications (7): 400, 689, 791, 794, 1148, 1396, 1399

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 351 (showing top): AGGAAGC_MIR5163P, CREL_01, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, GOBP_NEURON_PROJECTION_EXTENSION, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, XU_GH1_AUTOCRINE_TARGETS_UP, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, GOBP_INSULIN_SECRETION, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, AAGCCAT_MIR135A_MIR135B, GOBP_GROWTH, GOBP_REGULATION_OF_EXOCYTOSIS, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_CELLULAR_COMPONENT_MAINTENANCE, GOBP_NEUROTRANSMITTER_TRANSPORT

GO Biological Process (17): intracellular protein transport (GO:0006886), adenylate cyclase-modulating G protein-coupled receptor signaling pathway (GO:0007188), obsolete synaptic vesicle docking (GO:0016081), synaptic vesicle priming (GO:0016082), calcium-ion regulated exocytosis (GO:0017156), regulation of exocytosis (GO:0017157), insulin secretion (GO:0030073), cell differentiation (GO:0030154), regulation of membrane potential (GO:0042391), calcium ion-regulated exocytosis of neurotransmitter (GO:0048791), spontaneous neurotransmitter secretion (GO:0061669), positive regulation of inhibitory postsynaptic potential (GO:0097151), positive regulation of dendrite extension (GO:1903861), regulation of synaptic vesicle exocytosis (GO:2000300), positive regulation of excitatory postsynaptic potential (GO:2000463), exocytosis (GO:0006887), maintenance of presynaptic active zone structure (GO:0048790)

GO Molecular Function (6): zinc ion binding (GO:0008270), small GTPase binding (GO:0031267), transmembrane transporter binding (GO:0044325), structural constituent of presynaptic active zone (GO:0098882), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (8): presynaptic membrane (GO:0042734), presynaptic active zone (GO:0048786), extracellular exosome (GO:0070062), presynaptic active zone cytoplasmic component (GO:0098831), plasma membrane (GO:0005886), membrane (GO:0016020), cell projection (GO:0042995), synapse (GO:0045202)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
synaptic vesicle exocytosis	3
cellular anatomical structure	3
presynaptic active zone	2
presynapse	2
intracellular protein localization	1
protein transport	1
intracellular transport	1
adenylate cyclase activity	1
G protein-coupled receptor signaling pathway	1
protein-containing complex assembly	1
exocytic process	1
regulated exocytosis	1
exocytosis	1
regulation of vesicle-mediated transport	1
regulation of secretion by cell	1
protein secretion	1
peptide hormone secretion	1
cellular developmental process	1
monoatomic ion transmembrane transport	1
regulation of biological quality	1
calcium-ion regulated exocytosis	1
neurotransmitter secretion	1
spontaneous synaptic transmission	1
positive regulation of nervous system process	1
inhibitory postsynaptic potential	1
modulation of inhibitory postsynaptic potential	1
positive regulation of cell growth	1
positive regulation of developmental growth	1
dendrite extension	1
regulation of dendrite extension	1
regulation of neurotransmitter secretion	1
regulation of regulated secretory pathway	1
positive regulation of signal transduction	1
excitatory postsynaptic potential	1
modulation of excitatory postsynaptic potential	1
vesicle-mediated transport	1
secretion by cell	1
vesicle fusion to plasma membrane	1
maintenance of synapse structure	1
presynaptic active zone organization	1

Protein interactions and networks

STRING

1880 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RIMS2	RIMBP2	O15034	951
RIMS2	TSPOAP1	O95153	932
RIMS2	RAPGEF4	Q8WZA2	929
RIMS2	RAB3A	P20336	925
RIMS2	RAB3C	Q96E17	873
RIMS2	UNC13A	Q9UPW8	811
RIMS2	ERC1	Q8IUD2	785
RIMS2	RABAC1	Q9UI14	761
RIMS2	UNC13B	O14795	741
RIMS2	PPFIA2	O75334	649
RIMS2	RIMBP3	Q9UFD9	620
RIMS2	CACNA1F	O60840	618
RIMS2	ERC2	O15083	594
RIMS2	RIMBP3B	A6NNM3	591
RIMS2	TSPO	P30536	589

IntAct

45 interactions, top by confidence:

A	B	Type	Score
E	RIMS2	psi-mi:“MI:0915”(physical association)	0.590
ESR2	FBLL1	psi-mi:“MI:0914”(association)	0.460
ABCC4	RIMS2	psi-mi:“MI:0407”(direct interaction)	0.440
ARHGEF16	RIMS2	psi-mi:“MI:0407”(direct interaction)	0.440
ASIC3	RIMS2	psi-mi:“MI:0407”(direct interaction)	0.440
ATP2B4	RIMS2	psi-mi:“MI:0407”(direct interaction)	0.440
CYSLTR2	RIMS2	psi-mi:“MI:0407”(direct interaction)	0.440
DGKK	RIMS2	psi-mi:“MI:0407”(direct interaction)	0.440
DGKZ	RIMS2	psi-mi:“MI:0407”(direct interaction)	0.440
DOCK4	RIMS2	psi-mi:“MI:0407”(direct interaction)	0.440
FRMPD4	RIMS2	psi-mi:“MI:0407”(direct interaction)	0.440
FZD7	RIMS2	psi-mi:“MI:0407”(direct interaction)	0.440
TAMALIN	RIMS2	psi-mi:“MI:0407”(direct interaction)	0.440
E6	RIMS2	psi-mi:“MI:0407”(direct interaction)	0.440
ORF putative E6	RIMS2	psi-mi:“MI:0407”(direct interaction)	0.440
KCNA5	RIMS2	psi-mi:“MI:0407”(direct interaction)	0.440
KIR3DL3	RIMS2	psi-mi:“MI:0407”(direct interaction)	0.440
MAP2K2	RIMS2	psi-mi:“MI:0407”(direct interaction)	0.440
PBK	RIMS2	psi-mi:“MI:0407”(direct interaction)	0.440
RALBP1	RIMS2	psi-mi:“MI:0407”(direct interaction)	0.440
RASSF6	RIMS2	psi-mi:“MI:0407”(direct interaction)	0.440
SLC15A5	RIMS2	psi-mi:“MI:0407”(direct interaction)	0.440
SLCO1C1	RIMS2	psi-mi:“MI:0407”(direct interaction)	0.440
TJP2	RIMS2	psi-mi:“MI:0407”(direct interaction)	0.440
Dlg4	RIMS2	psi-mi:“MI:0407”(direct interaction)	0.440
FYN	RIMS2	psi-mi:“MI:0915”(physical association)	0.400
GRB2	RIMS2	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (17): RAPGEF4 (Affinity Capture-Western), RIMS2 (Reconstituted Complex), YWHAH (Affinity Capture-Western), RIMS2 (Affinity Capture-Western), RIMS2 (Affinity Capture-RNA), RIMS2 (Affinity Capture-MS), RIMS2 (Protein-peptide), RIMS2 (Two-hybrid), RIMS2 (Affinity Capture-MS), RIMS2 (Affinity Capture-MS), RIMS2 (Cross-Linking-MS (XL-MS)), RIMS2 (Cross-Linking-MS (XL-MS)), RIMS2 (Affinity Capture-MS), RIMS2 (Two-hybrid), RIMS2 (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A0A0K3AV08, A2CEX1, A8XU52, E1BLT8, E7FBS9, E9QCD3, E9QDC5, F5HB62, G5EDE9, G5EEK3, O01700, O14490, O62090, P62024, P97836, P97839, Q2M3X8, Q2THW0, Q2THW7, Q2THW8, Q2THW9, Q2THX0, Q2THX1, Q571K4, Q5HZJ0, Q5R838, Q5RFW2, Q5RJX2, Q5Y5T5, Q66624, Q6PEI3, Q7ZXH3, Q7ZYZ6, Q8BJ42, Q8BQQ1, Q8IZN3, Q8VDZ4, Q8WQC0, Q91ZP3, Q96SK2

Diamond homologs: A0A075F932, A0FGR8, A0FGR9, A4IJ05, A6QP06, O00443, O00445, O00750, O08625, O08835, O35681, P04409, P05128, P05129, P10829, P21521, P21579, P21707, P24505, P24506, P24507, P29101, P34693, P40748, P40749, P41823, P46096, P46097, P47191, P47708, P47709, P47861, P48018, P50232, P59926, P63318, P63319, P70169, P70610, P70611

SIGNOR signaling

9 interactions.

A	Effect	B	Mechanism
RIMS2	“up-regulates activity”	CACNA1D	binding
RIMS2	“up-regulates activity”	RAB3A	relocalization
RIMS2	“up-regulates activity”	RAB3C	relocalization
RIMS2	“up-regulates activity”	UNC13B	relocalization
RIMBP3	“down-regulates activity”	RIMS2	binding
RIMBP2	“down-regulates activity”	RIMS2	binding
RIMBP3C	“down-regulates activity”	RIMS2	binding
TSPOAP1	“down-regulates activity”	RIMS2	binding
RIMBP3B	“down-regulates activity”	RIMS2	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 43 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
RAF/MAP kinase cascade	5	11.7×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	2
Uncertain significance	187
Likely benign	14
Benign	5

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
974607	NM_001348484.3(RIMS2):c.3126G>A (p.Trp1042Ter)	Pathogenic
974608	NM_001348484.3(RIMS2):c.2884C>T (p.Arg962Ter)	Pathogenic
974609	NM_001348484.3(RIMS2):c.4363+1G>A	Pathogenic
974610	NM_001348484.3(RIMS2):c.3508C>T (p.Arg1170Ter)	Pathogenic
974611	NM_001348484.3(RIMS2):c.1595C>G (p.Ser532Ter)	Pathogenic
2160448	NM_001348484.3(RIMS2):c.2995+2T>C	Likely pathogenic
3899379	NM_001348484.3(RIMS2):c.208C>T (p.Gln70Ter)	Likely pathogenic

SpliceAI

7510 predictions. Top by Δscore:

Variant	Effect	Δscore
8:103501056:TGCTC:T	donor_gain	1.0000
8:103501062:AG:A	donor_loss	1.0000
8:103501063:G:GG	donor_gain	1.0000
8:103501063:G:T	donor_loss	1.0000
8:103652708:GAC:G	donor_gain	1.0000
8:103652711:G:GG	donor_gain	1.0000
8:103652715:G:GG	donor_gain	1.0000
8:103697083:CAGA:C	acceptor_loss	1.0000
8:103697084:A:AC	acceptor_loss	1.0000
8:103697084:A:AG	acceptor_gain	1.0000
8:103697085:G:A	acceptor_loss	1.0000
8:103697085:G:GA	acceptor_gain	1.0000
8:103697085:GA:G	acceptor_gain	1.0000
8:103697085:GAA:G	acceptor_gain	1.0000
8:103697085:GAAA:G	acceptor_gain	1.0000
8:103697085:GAAAA:G	acceptor_gain	1.0000
8:103697272:TC:T	donor_gain	1.0000
8:103697293:CAAG:C	donor_loss	1.0000
8:103697294:AAGG:A	donor_loss	1.0000
8:103697295:AGGT:A	donor_loss	1.0000
8:103697297:G:A	donor_loss	1.0000
8:103766223:GCAG:G	acceptor_loss	1.0000
8:103766224:CAG:C	acceptor_loss	1.0000
8:103766225:A:AG	acceptor_gain	1.0000
8:103766225:A:C	acceptor_loss	1.0000
8:103766226:G:GG	acceptor_gain	1.0000
8:103766226:GGTT:G	acceptor_gain	1.0000
8:103766533:GACAG:G	donor_gain	1.0000
8:103882588:AGT:A	acceptor_gain	1.0000
8:103882589:GTG:G	acceptor_gain	1.0000

AlphaMissense

10497 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000001227 (8:103973207 G>A), RS1000008662 (8:104209122 G>C), RS1000013932 (8:103654883 C>T), RS1000014602 (8:104134133 A>G), RS1000017150 (8:103730048 A>G), RS1000018445 (8:104034431 A>G), RS1000019921 (8:103599450 T>G), RS1000020323 (8:103535469 A>G), RS1000021418 (8:103772052 A>G), RS1000021591 (8:103725683 G>C), RS1000022347 (8:103948730 A>G), RS1000022430 (8:103938934 T>C), RS1000022821 (8:103786175 G>A,C), RS1000028753 (8:103820390 C>A,T), RS1000030936 (8:103655933 T>A,C)

Disease associations

OMIM: gene MIM:606630 | disease phenotypes: MIM:610427, MIM:618970

GenCC curated gene-disease

Disease	Classification	Inheritance
cone-rod synaptic disorder syndrome, congenital nonprogressive	Strong	Autosomal recessive
cone-rod synaptic disorder, congenital nonprogressive	Strong	Autosomal recessive

Mondo (3): cone-rod synaptic disorder, congenital nonprogressive (MONDO:0012490), primary ovarian failure (MONDO:0005387), cone-rod synaptic disorder syndrome, congenital nonprogressive (MONDO:0033543)

Orphanet (2): Congenital stationary night blindness (Orphanet:215), NON RARE IN EUROPE: Primary ovarian failure (Orphanet:619)

HPO phenotypes

12 total (12 of 12 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000543	Optic disc pallor
HP:0000613	Photophobia
HP:0000639	Nystagmus
HP:0000729	Autistic behavior
HP:0000739	Anxiety
HP:0000750	Delayed speech and language development
HP:0001251	Ataxia
HP:0001263	Global developmental delay
HP:0003074	Hyperglycemia
HP:0007663	Reduced visual acuity
HP:0030329	Retinal thinning on OCT

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST002142_2	Cocaine dependence	3.000000e-06
GCST003783_7	Multiple system atrophy (pathologically confirmed)	4.000000e-06
GCST007202_2	High density lipoprotein cholesterol levels	2.000000e-06
GCST007824_5	Monoclonal gammopathy of undetermined significance	3.000000e-06
GCST010396_5	Gut microbiota (bacterial taxa, hurdle binary method)	9.000000e-06
GCST010600_3	Dietary fat liking	2.000000e-06
GCST011823_8	Parkinson’s disease progression (cognitive)	3.000000e-11

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0007874	gut microbiome measurement
EFO:0010816	dietary fat liking measurement
EFO:0008336	disease progression measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D016649	Primary Ovarian Insufficiency	C12.050.351.500.056.630.750; C12.100.250.056.630.750; C19.391.630.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	7
trichostatin A	affects cotreatment, increases expression	3
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	3
sodium arsenite	decreases expression, affects methylation	2
aristolochic acid I	decreases expression	1
methyleugenol	decreases expression	1
bisphenol A	affects cotreatment, increases methylation	1
kojic acid	decreases expression	1
benzo(e)pyrene	decreases methylation	1
N,N,N’,N’-tetrakis(2-pyridylmethyl)ethylenediamine	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
bisphenol S	decreases methylation	1
Rosiglitazone	decreases expression	1
Zoledronic Acid	affects cotreatment, increases expression	1
Arsenic Trioxide	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Fluvastatin	affects cotreatment, increases expression	1
Atrazine	decreases expression	1
Curcumin	decreases expression	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Diethylhexyl Phthalate	increases expression	1
Methapyrilene	decreases methylation	1
Nickel	decreases expression	1
Aflatoxin B1	decreases methylation	1
Zinc Sulfate	decreases expression	1
Okadaic Acid	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00417066	PHASE4	COMPLETED	Flexible GnRH Antagonist vs Flare up GnRH Agonist Protocol in Poor Responders
NCT00732693	PHASE4	COMPLETED	Evaluation of Physiologic and Standard Sex Steroid Replacement Regimens in Women With Premature Ovarian Failure
NCT00837616	PHASE4	COMPLETED	Estrogen Dosing in Turner Syndrome: Pharmacology and Metabolism
NCT01853501	PHASE4	UNKNOWN	Effects of ADSC Therapy in Women With POF
NCT02783937	PHASE4	COMPLETED	Filgrastim for Premature Ovarian Insufficiency
NCT03535480	PHASE4	UNKNOWN	Autologous Bone Marrow Stem Cell Ovarian Transplantation to Restore Ovarian Function in Premature Ovarian Failure
NCT00140998	PHASE3	COMPLETED	Estrogen Treatment (Oral vs. Patches) in Turner Syndrome
NCT00001951	PHASE2	COMPLETED	Hormone Replacement in Young Women With Premature Ovarian Failure
NCT00370019	PHASE2	WITHDRAWN	Effects of an Estrogen Replacement Therapy Skin Patch on Ovulation in Women With Premature Ovarian Failure
NCT00429494	PHASE2	COMPLETED	GnRH Analogue for Ovarian Function Preservation in Hematopoietic Stem Cell Transplantation Patients
NCT03816852	PHASE2	SUSPENDED	The Safety and Efficiency Study of Mesenchymal Stem Cell (19#iSCLife®-POI) in Premature Ovarian Insufficiency
NCT04536467	PHASE2	UNKNOWN	Prevention of Chemotherapy-Induced Ovarian Failure With Goserelin in Premenopausal Lymphoma Patients
NCT06117982	PHASE2	COMPLETED	The Impact of Granulocyte Colony Stimulating Factor on Premature Ovarian Insufficiency
NCT02912104	PHASE1	COMPLETED	A Therapeutic Trial of Human Amniotic Epithelial Cells Transplantation for Primary Ovarian Failure
NCT03178695	PHASE1	COMPLETED	Inovium Ovarian Rejuvenation Trials
NCT04815213	PHASE1	ACTIVE_NOT_RECRUITING	The Use of Expandeded Mesenchymal Stromal Cells (MSC) in Premature Ovarian Failure (POF) in Adult Humans
NCT05138367	PHASE1	COMPLETED	Effects of UCA-PSCs in Women With POF
NCT06132542	PHASE1	UNKNOWN	Autologous ADMSC Transplantation in Patients With POI
NCT00948857	PHASE2/PHASE3	TERMINATED	Dehydroepiandrosterone (DHEA) Treatment and Premature Ovarian Failure (POF)
NCT04031456	PHASE2/PHASE3	RECRUITING	Autologous PRP Infusion May Restore Ovarian Function and May Promote Folliculogenesis in POI Patients
NCT02043743	PHASE1/PHASE2	UNKNOWN	Autologous Stem Cells Transplantation in Patients With Idiopathic and Drug Induced Premature Ovarian Failure
NCT02062931	PHASE1/PHASE2	UNKNOWN	Autologous Mesenchymal Stem Cells Transplantation In Women With Premature Ovarian Failure
NCT02151890	PHASE1/PHASE2	COMPLETED	Pregnancy After Stem Cell Transplantation in Premature Ovarian Failure
NCT02372474	PHASE1/PHASE2	COMPLETED	It is a Real The First Baby Of Autologous Stem Cell Therapy in Premature Ovarian Failure
NCT02603744	PHASE1/PHASE2	UNKNOWN	Autologous Adipose Derived Mesenchymal Stromal Cells Transplantation in Women With Premature Ovarian Failure (POF)
NCT02644447	PHASE1/PHASE2	COMPLETED	Transplantation of HUC-MSCs With Injectable Collagen Scaffold for POF
NCT03069209	PHASE1/PHASE2	UNKNOWN	Autologous Bone Marrow-Derived Stem Cell Transplantation in Patients With Premature Ovarian Failure (POF)
NCT03985462	PHASE1/PHASE2	WITHDRAWN	Very Small Embryonic-like Stem Cells for Ovary
NCT04009473	PHASE1/PHASE2	UNKNOWN	Stem Cell Therapy and Growth Factor Ovarian in Vitro Activation
NCT04071574	PHASE1/PHASE2	COMPLETED	Comparative Study on the Efficacy of Ovarian Stimulation Protocols on the Success Rate of ICSI in Female Infertility
NCT04922398	PHASE1/PHASE2	UNKNOWN	Ovarian Injection of PRP (Platelet -Rich Plasma) Vs Normal Saline in Premature Ovarian Insufficiency
NCT05462379	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Autologous Heterotopic Fresh Ovarian Graft in Woman With LACC Eligible for Pelvic Radiotherapy Treatment.
NCT06202547	PHASE1/PHASE2	UNKNOWN	Intra-ovarian Injection of MSC-EVs in Idiopathic Premature Ovarian Failure
NCT01129947	EARLY_PHASE1	WITHDRAWN	The Use of DHEA in Women With Premature Ovarian Failure
NCT05522634	EARLY_PHASE1	UNKNOWN	A Clinical Study of Chinese Herbal Compound TJAOA101 in the Treatment of Premature Ovarian Insufficiency
NCT07308327	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	The Influence of Gut Microbiota on Ovarian Function: A Single-center, Randomized,Double Blind, Parallel-controlled, Exploratory Clinical Trial
NCT00001275	Not specified	COMPLETED	Ovarian Follicle Function in Patients With Primary Ovarian Failure
NCT00001306	Not specified	COMPLETED	Steroid Therapy in Autoimmune Premature Ovarian Failure
NCT00006156	Not specified	COMPLETED	Feasibility Study for Development of an Early Test for Ovarian Failure
NCT00119925	Not specified	UNKNOWN	‘SPRING’-Study: Subfertility Guidelines: Patient Related Implementation in the Netherlands Among Gynaecologists