SIAH3

Chr 13

siah E3 ubiquitin protein ligase family member 3

NCBI Gene: 283514ENSG00000215475UniProt: Q8IW03OMIM: 615609

SIAH3 encodes an E3 ubiquitin ligase that negatively regulates PINK1 protein stability and prevents PRKN translocation to damaged mitochondria. Mutations cause autosomal recessive early-onset Parkinson disease, presenting in childhood or adolescence with progressive movement disorder. The gene shows low constraint to loss-of-function variation (pLI 0.001, LOEUF 1.59), consistent with recessive inheritance requiring biallelic mutations.

OMIMResearchSummary from RefSeq, UniProt
DNmechanismLOEUF 1.59
Clinical Summary— SIAH3
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
55 unique Pathogenic / Likely Pathogenic· 56 VUS of 120 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
1.59LOEUF
pLI 0.001
Z-score 0.51
OE 0.78 (0.41–1.59)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint
-0.35Z-score
OE missense 1.07 (0.95–1.21)
188 obs / 175.0 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios
LoF OE0.78 (0.41–1.59)
0≤0.351.4
Missense OE1.07 (0.95–1.21)
0≤0.61.4
Synonymous OE0.95
0≤1.21.6
LoF obs/exp: 5 / 6.4Missense obs/exp: 188 / 175.0Syn Z: 0.36
DN
0.6453th %ile
GOF
0.4481th %ile
LOF
0.54top 25%

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction 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

120 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic54
Likely Pathogenic1
VUS56
Likely Benign5
54
Pathogenic
1
Likely Pathogenic
56
VUS
5
Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
54
0
54
Likely Pathogenic
0
0
1
0
1
VUS
0
54
2
0
56
Likely Benign
0
3
2
0
5
Benign
0
0
0
0
0
Total057590116

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

View in ClinVar →

Protein Context — Lollipop Plot

SIAH3 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 3 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 4 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients