SIAH3

Chr 13

siah E3 ubiquitin protein ligase family member 3

NCBI Gene: 283514 ENSG00000215475 UniProt: Q8IW03

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.

ResearchSummary from RefSeq, UniProt

Predicted to enable ubiquitin conjugating enzyme binding activity and ubiquitin protein ligase activity. Involved in obsolete negative regulation of protein targeting to mitochondrion and regulation of protein stability. Located in mitochondrion. [provided by Alliance of Genome Resources, Jun 2026]

ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.59

LOEUF

Mechanism· predicted

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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 OE?0.78 (0.41–1.59)

0≤0.351.4

Missense OE?1.07 (0.95–1.21)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 5 / 6.4Missense obs/exp: 188 / 175.0Syn Z: 0.36

Background carrier burden — how many people carry a rare variant somewhere in SIAH3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 280

415 rare PASS variants

Rare truncating (LoF)

1 in 6,800

36 rare PASS variants

Rare synonymous (reference)

1 in 640

166 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SIAH3. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 320	1 in 6,200
South Asian	~43k	1 in 170	1 in 8,500
Remaining (unassigned)	~30k	1 in 240	1 in 4,300
European (Finnish)	~27k	1 in 830	≈ 1 in 26,000
Admixed American	~22k	1 in 220	none seen
African / African American	~21k	1 in 130	1 in 1,500
East Asian	~20k	1 in 280	≈ 1 in 6,600
Ashkenazi Jewish	~13k	1 in 330	≈ 1 in 3,200
Middle Eastern	~2,884	1 in 360	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 2 coding exons well covered in gnomAD exomes and genomes.? see exons ↓