RUFY3

Chr 4

RUN and FYVE domain containing 3

Also known as: RIPX, SINGAR1, ZFYVE30

NCBI Gene: 22902 ENSG00000018189 UniProt: Q7L099 OMIM: 611194

RUFY3 encodes a protein that promotes retrograde transport of endolysosomes along microtubules and is required for maintenance of neuronal polarity and axon formation. Mutations cause autosomal recessive neurodevelopmental disorders with intellectual disability, developmental delay, and neurological features. This gene is highly constrained against loss-of-function variants, indicating intolerance to protein-disrupting mutations.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a RPIP8, UNC-14, and NESCA domain-containing protein that is required for maintenance of neuronal polarity. In addition, it has been implicated in mediation of gastric cancer cell migration and invasion via interaction with P21-activated kinase-1, which promotes its expression. The encoded protein localizes to F-actin-enriched invadopodia to induce formation of protrusions, thereby facilitating cell migration. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2016]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.46

Clinical Summary— RUFY3

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.28) despite low pLI — interpret in context.

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ClinVar Variants

68 VUS of 101 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.46LOEUF

pLI 0.021

Z-score 4.22

OE 0.28 (0.17–0.46)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.48Z-score

OE missense 0.61 (0.55–0.69)

202 obs / 328.7 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.28 (0.17–0.46)

0≤0.351.4

Missense OE?0.61 (0.55–0.69)

0≤0.61.4

Synonymous OE?0.92

0≤1.21.6

LoF obs/exp: 11 / 39.7Missense obs/exp: 202 / 328.7Syn Z: 0.68

This gene — mechanism propensity

0.78top 25%

GOF

0.72top 25%

LOF

0.3162th %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

101 submitted variants in ClinVar

ClinVar

Classification Summary

VUS68

Likely Benign3

Benign2

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	1	67	0	0	68
Likely Benign	0	2	0	1	3
Benign	0	0	2	0	2
Total	1	69	2	1	73

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

View in ClinVar →

23 pathogenic / likely-pathogenic (of 36) ClinVar copy-number / structural variants overlap RUFY3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →