RNF19A

Chr 8

ring finger protein 19A, RBR E3 ubiquitin protein ligase

Also known as: RNF19

NCBI Gene: 25897 ENSG00000034677 UniProt: Q9NV58 OMIM: 607119

The protein functions as an E3 ubiquitin ligase that targets specific substrates including synphilin-1 and pathogenic SOD1 variants for proteasomal degradation. Mutations cause autosomal recessive spastic paraplegia, which primarily affects the corticospinal tracts leading to progressive lower limb spasticity and weakness. This gene is highly constrained against loss-of-function variants, suggesting that complete protein loss is not well tolerated.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the ring between ring fingers (RBR) protein family, and the encoded protein contains two RING-finger motifs and an in between RING fingers motif. This protein is an E3 ubiquitin ligase that is localized to Lewy bodies, and ubiquitylates synphilin-1, which is an interacting protein of alpha synuclein in neurons. The encoded protein may be involved in amyotrophic lateral sclerosis and Parkinson's disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.47

Clinical Summary— RNF19A

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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

72 VUS of 91 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.47LOEUF

pLI 0.025

Z-score 4.00

OE 0.28 (0.17–0.47)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.38Z-score

OE missense 0.69 (0.63–0.76)

322 obs / 466.7 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.28 (0.17–0.47)

0≤0.351.4

Missense OE?0.69 (0.63–0.76)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 10 / 35.9Missense obs/exp: 322 / 466.7Syn Z: -0.06

This gene — mechanism propensity

0.7130th %ile

GOF

0.7028th %ile

LOF

0.4628th %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

91 submitted variants in ClinVar

ClinVar

Classification Summary

VUS72

Likely Benign2

Benign1

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	72	0	72
Likely Benign	2	0	2
Benign	0	1	1
Total	74	1	75

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

View in ClinVar →

37 pathogenic / likely-pathogenic (of 43) ClinVar copy-number / structural variants overlap RNF19A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →