RIMS2

Chr 8AR

regulating synaptic membrane exocytosis 2

Also known as: CRSDS, OBOE, RAB3IP3, RIM2

NCBI Gene: 9699 ENSG00000176406 UniProt: Q9UQ26 OMIM: 606630

RIMS2 encodes a presynaptic scaffold protein that regulates neurotransmitter release by interacting with RAB3 and other synaptic proteins involved in exocytosis. Biallelic mutations cause cone-rod synaptic disorder syndrome, a congenital nonprogressive condition affecting retinal photoreceptor synapses and leading to visual impairment from birth. This gene is highly constrained against loss-of-function variants (pLI ~1.0, LOEUF 0.21) and follows autosomal recessive inheritance.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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. [provided by RefSeq, Feb 2017]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.211 OMIM phenotype

Clinical Summary— RIMS2

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

7 unique Pathogenic / Likely Pathogenic· 194 VUS of 244 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.21LOEUF

pLI 1.000

Z-score 7.38

OE 0.12 (0.07–0.21)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

0.78Z-score

OE missense 0.92 (0.86–0.98)

697 obs / 757.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.12 (0.07–0.21)

0≤0.351.4

Missense OE?0.92 (0.86–0.98)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 10 / 82.2Missense obs/exp: 697 / 757.1Syn Z: -0.56

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongRIMS2-related syndromic congenital cone-rod synaptic diseaseLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.4983th %ile

GOF

0.5269th %ile

LOF

0.76top 10%

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

244 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5

Likely Pathogenic2

VUS194

Likely Benign19

Benign6

Conflicting2

Pathogenic

Likely Pathogenic

194

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	5	0	0	0	5
Likely Pathogenic	2	0	0	0	2
VUS	1	192	0	1	194
Likely Benign	0	4	6	9	19
Benign	0	2	0	4	6
Conflicting	—				2
Total	8	198	6	14	228

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

39 pathogenic / likely-pathogenic (of 51) ClinVar copy-number / structural variants overlap RIMS2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →