RUVBL1

Chr 3

RuvB like AAA ATPase 1

Also known as: ECP-54, ECP54, INO80H, NMP 238, NMP238, PONTIN, Pontin52, RVB1

NCBI Gene: 8607 ENSG00000175792 UniProt: Q9Y265 OMIM: 603449

The protein functions as a DNA-dependent ATPase and helicase that is essential for chromatin remodeling, histone modification, and transcriptional regulation through its role in multiple nuclear complexes including NuA4 and INO80. Mutations cause autosomal dominant neurodevelopmental disorders with intellectual disability, developmental delay, and variable features including seizures and behavioral abnormalities. This gene is highly constrained against loss-of-function variants, indicating that haploinsufficiency is not well tolerated.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a protein that has both DNA-dependent ATPase and DNA helicase activities and belongs to the ATPases associated with diverse cellular activities (AAA+) protein family. The encoded protein associates with several multisubunit transcriptional complexes and with protein complexes involved in both ATP-dependent remodeling and histone modification. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.19

Clinical Summary— RUVBL1

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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

4 unique Pathogenic / Likely Pathogenic· 97 VUS of 224 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.19LOEUF

pLI 0.999

Z-score 4.40

OE 0.04 (0.01–0.19)

Highly constrained

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

Missense Constraint?

3.39Z-score

OE missense 0.41 (0.35–0.48)

107 obs / 260.9 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.04 (0.01–0.19)

0≤0.351.4

Missense OE?0.41 (0.35–0.48)

0≤0.61.4

Synonymous OE?1.09

0≤1.21.6

LoF obs/exp: 1 / 24.5Missense obs/exp: 107 / 260.9Syn Z: -0.72

This gene — mechanism propensity

0.5870th %ile

GOF

0.2696th %ile

LOF

0.70top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.19

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

224 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

Likely Pathogenic2

VUS97

Likely Benign83

Benign13

Conflicting3

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	1	0	0	2
Likely Pathogenic	0	2	0	0	2
VUS	1	90	4	2	97
Likely Benign	0	0	29	54	83
Benign	0	0	11	2	13
Conflicting	—				3
Total	2	93	44	58	200

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

View in ClinVar →

12 pathogenic / likely-pathogenic (of 19) ClinVar copy-number / structural variants overlap RUVBL1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →