RIMS3

Chr 1

regulating synaptic membrane exocytosis 3

Also known as: NIM3, RIM 3, RIM3

NCBI Gene: 9783 ENSG00000117016 UniProt: Q9UJD0 OMIM: 611600

The RIMS3 protein regulates synaptic membrane exocytosis and serves as a structural constituent of the presynaptic active zone, where it controls synaptic vesicle release. Mutations in RIMS3 cause autosomal recessive cone-rod dystrophy, a retinal disorder affecting photoreceptor function. The gene shows tolerance to loss-of-function variants (pLI = 0.0001), consistent with a recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable transmembrane transporter binding activity. Predicted to be a structural constituent of presynaptic active zone. Predicted to be involved in several processes, including regulated exocytosis; regulation of synapse organization; and regulation of synaptic vesicle exocytosis. Predicted to be located in presynaptic active zone. Predicted to be active in several cellular components, including postsynaptic cytosol; presynaptic active zone cytoplasmic component; and presynaptic membrane. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.06

Clinical Summary— RIMS3

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

📋

ClinVar Variants

55 VUS of 74 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.06LOEUF

pLI 0.000

Z-score 1.41

OE 0.59 (0.34–1.06)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.97Z-score

OE missense 0.81 (0.71–0.92)

162 obs / 200.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.59 (0.34–1.06)

0≤0.351.4

Missense OE?0.81 (0.71–0.92)

0≤0.61.4

Synonymous OE?0.83

0≤1.21.6

LoF obs/exp: 8 / 13.6Missense obs/exp: 162 / 200.8Syn Z: 1.20

This gene — mechanism propensity

0.75top 25%

GOF

0.7127th %ile

LOF

0.4627th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

74 submitted variants in ClinVar

ClinVar

Classification Summary

VUS55

Likely Benign8

Benign5

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	55	0	0	55
Likely Benign	3	1	4	8
Benign	2	1	2	5
Total	60	2	6	68

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

View in ClinVar →

9 pathogenic / likely-pathogenic (of 16) ClinVar copy-number / structural variants overlap RIMS3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →