SIAH2

Chr 3

siah E3 ubiquitin protein ligase 2

Also known as: hSiah2

NCBI Gene: 6478 ENSG00000181788 UniProt: O43255 OMIM: 602213

This gene encodes a protein that is a member of the seven in absentia homolog (SIAH) family. The protein is an E3 ligase and is involved in ubiquitination and proteasome-mediated degradation of specific proteins. The activity of this ubiquitin ligase has been implicated in regulating cellular response to hypoxia. [provided by RefSeq, Jul 2008]

OMIM Research

OMIM ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.59

LOEUF

LOF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.59LOEUF

pLI 0.687

Z-score 2.31

OE 0.12 (0.04–0.59)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.43Z-score

OE missense 0.48 (0.40–0.57)

81 obs / 170.1 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.12 (0.04–0.59)

0≤0.351.4

Missense OE?0.48 (0.40–0.57)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 1 / 8.1Missense obs/exp: 81 / 170.1Syn Z: 0.23

Background carrier burden — how many people carry a rare variant somewhere in SIAH2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 240

297 rare PASS variants

Rare truncating (LoF)

1 in 26,000

17 rare PASS variants

Rare synonymous (reference)

1 in 250

183 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SIAH2. 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 220	1 in 23,000
South Asian	~43k	1 in 170	≈ 1 in 16,000
Remaining (unassigned)	~30k	1 in 430	none seen
European (Finnish)	~27k	1 in 420	none seen
Admixed American	~22k	1 in 360	none seen
African / African American	~21k	1 in 260	none seen
East Asian	~20k	1 in 280	none seen
Ashkenazi Jewish	~13k	1 in 1,600	≈ 1 in 12,000
Middle Eastern	~2,884	1 in 250	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): 1 of 2 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: all 2.? see exons ↓