SIAH3

Summary

SIAH3 (siah E3 ubiquitin protein ligase family member 3, HGNC:30553) is a protein-coding gene on chromosome 13q14.13, encoding Seven in absentia homolog 3 (Q8IW03). Negative regulator of PRKN translocation to damaged mitochondria.

Predicted to enable ubiquitin conjugating enzyme binding activity and ubiquitin protein ligase activity. Involved in negative regulation of protein targeting to mitochondrion and regulation of protein stability. Located in mitochondrion and nucleoplasm.

Source: NCBI Gene 283514 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 64 total
• MANE Select transcript: NM_198849

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30553
Approved symbol	SIAH3
Name	siah E3 ubiquitin protein ligase family member 3
Location	13q14.13
Locus type	gene with protein product
Status	Approved
Aliases	FLJ39203
Ensembl gene	ENSG00000215475
Ensembl biotype	protein_coding
OMIM	615609
Entrez	283514

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000400405

RefSeq mRNA: 1 — MANE Select: NM_198849 NM_198849

CCDS: CCDS41883

Canonical transcript exons

ENST00000400405 — 2 exons

Exon	Start	End
ENSE00001542761	45777242	45784057
ENSE00001542763	45851495	45851753

Expression profiles

Bgee: expression breadth broad, 82 present calls, max score 80.64.

FANTOM5 (CAGE): breadth broad, TPM avg 1.0884 / max 72.1278, expressed in 212 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
137109	0.6709	182
137108	0.4176	124

Top tissues by expression

221 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	80.64	gold quality
buccal mucosa cell	CL:0002336	79.40	silver quality
oviduct epithelium	UBERON:0004804	71.67	gold quality
right uterine tube	UBERON:0001302	70.76	gold quality
substantia nigra pars reticulata	UBERON:0001966	70.72	gold quality
substantia nigra pars compacta	UBERON:0001965	69.07	gold quality
prefrontal cortex	UBERON:0000451	65.55	gold quality
fallopian tube	UBERON:0003889	65.26	gold quality
bronchial epithelial cell	CL:0002328	64.75	gold quality
bronchus	UBERON:0002185	63.64	gold quality
caput epididymis	UBERON:0004358	62.06	gold quality
right hemisphere of cerebellum	UBERON:0014890	61.73	gold quality
ganglionic eminence	UBERON:0004023	61.52	gold quality
frontal cortex	UBERON:0001870	60.73	gold quality
cerebellum	UBERON:0002037	60.72	gold quality
neocortex	UBERON:0001950	60.52	gold quality
cerebellar cortex	UBERON:0002129	59.96	gold quality
pons	UBERON:0000988	59.93	gold quality
cerebellar hemisphere	UBERON:0002245	59.64	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	59.48	gold quality
anterior cingulate cortex	UBERON:0009835	59.03	gold quality
Brodmann (1909) area 9	UBERON:0013540	58.94	gold quality
cerebellar vermis	UBERON:0004720	58.22	silver quality
right frontal lobe	UBERON:0002810	58.10	gold quality
cerebral cortex	UBERON:0000956	57.89	gold quality
substantia nigra	UBERON:0002038	57.31	gold quality
primary visual cortex	UBERON:0002436	56.99	gold quality
caudate nucleus	UBERON:0001873	56.25	gold quality
midbrain	UBERON:0001891	56.24	gold quality
occipital lobe	UBERON:0002021	55.81	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-93593	yes	7.08
E-ANND-3	yes	3.91
E-MTAB-7303	no	60.50

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

112 targeting SIAH3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-6753-3P	99.93	66.57	637
HSA-MIR-7107-3P	99.93	66.73	627
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-6499-3P	99.90	66.38	1212
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-6857-5P	99.87	65.32	985
HSA-MIR-3663-3P	99.84	70.39	798
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-4799-5P	99.82	70.60	2663
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712

Literature-anchored findings (GeneRIF, showing 2)

• SIAH3 expression is significantly downregulated in human masticatory mucosa during wound healing (PMID:28005267)
• Genome-wide association study identifies SIAH3 locus influencing the rate of ventricular enlargement in non-demented elders. (PMID:31711042)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Siah3	ENSMUSG00000091722
rattus_norvegicus	Siah3	ENSRNOG00000082882

Paralogs (3): SIAH2 (ENSG00000181788), ZSWIM9 (ENSG00000185453), SIAH1 (ENSG00000196470)

Protein

Protein identifiers

Seven in absentia homolog 3 — Q8IW03 (reviewed: Q8IW03)

All UniProt accessions (1): Q8IW03

UniProt curated annotations — full annotation on UniProt →

Function. Negative regulator of PRKN translocation to damaged mitochondria. Acts probably by destabilizing PINK1 protein, hence inhibiting PRKN targeting to dysfunctional depolarized mitochondria.

Subcellular location. Mitochondrion.

Similarity. Belongs to the SINA (Seven in absentia) family.

RefSeq proteins (1): NP_942146* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004162	SINA-like_animal	Family
IPR008974	TRAF-like	Homologous_superfamily
IPR018121	7-in-absentia-prot_TRAF-dom	Domain

Pfam: PF03145

UniProt features (6 total): binding site 4, chain 1, zinc finger region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IW03-F1	72.55	0.51

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (4): 107; 114; 126; 131

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 121 (showing top): RRAGTTGT_UNKNOWN, YAATNRNNNYNATT_UNKNOWN, FREAC2_01, GOBP_PROTEIN_TARGETING, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, LHX3_01, FOXO1_01, CHX10_01, CEBPB_01, NKX61_01, CDP_01, CEBP_Q2, TGCTGAY_UNKNOWN, GOBP_NEGATIVE_REGULATION_OF_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION

GO Biological Process (5): regulation of protein stability (GO:0031647), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), obsolete negative regulation of protein targeting to mitochondrion (GO:1903215), ubiquitin-dependent protein catabolic process (GO:0006511), multicellular organism development (GO:0007275)

GO Molecular Function (5): zinc ion binding (GO:0008270), ubiquitin conjugating enzyme binding (GO:0031624), ubiquitin protein ligase activity (GO:0061630), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (3): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), mitochondrion (GO:0005739)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
regulation of biological quality	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
protein ubiquitination	1
modification-dependent protein catabolic process	1
multicellular organismal process	1
anatomical structure development	1
transition metal ion binding	1
ubiquitin-like protein conjugating enzyme binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
binding	1
cation binding	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

450 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SIAH3	TOMM7	Q9P0U1	633
SIAH3	BAG4	O95429	612
SIAH3	HSPA1L	P34931	571
SIAH3	PINK1	Q9BXM7	512
SIAH3	KIAA0408	Q6ZU52	397
SIAH3	FAM217A	Q8IXS0	396
SIAH3	PP2D1	A8MPX8	388
SIAH3	ARL9	Q6T311	380
SIAH3	GMDS	O60547	371
SIAH3	OR6M1	Q8NGM8	370
SIAH3	HS3ST4	Q9Y661	370
SIAH3	MS4A5	Q9H3V2	367
SIAH3	DNAJC12	Q9UKB3	365
SIAH3	TP53	P04637	350
SIAH3	RSPH10B2	B2RC85	350

IntAct

4 interactions, top by confidence:

A	B	Type	Score
KRTAP6-2	SIAH3	psi-mi:“MI:0915”(physical association)	0.560
SIAH3	KRTAP6-2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (9): SIAH3 (Two-hybrid), SIAH3 (Positive Genetic), SIAH3 (Affinity Capture-MS), PINK1 (Co-purification), PINK1 (Affinity Capture-Western), SIAH3 (Affinity Capture-Western), SIAH3 (Reconstituted Complex), SIAH1 (Affinity Capture-Western), SIAH2 (Affinity Capture-Western)

ESM2 similar proteins: A8X679, M9MRI4, O08722, O43255, P0DTL6, P0DW87, P0DW89, P0DW91, P21461, P29304, P61092, P61093, P93748, Q06985, Q06986, Q08CH8, Q10L91, Q2TAD9, Q3MV19, Q4U5R4, Q505D9, Q6GNX1, Q6IWL4, Q6J1I8, Q6J212, Q6J2U6, Q6ZTA4, Q7SYL3, Q7ZVG6, Q84JL3, Q86MW9, Q8C7M3, Q8I147, Q8IUQ4, Q8IW03, Q8K1S3, Q8K2J9, Q8R4T2, Q8S3N1, Q8T3Y0

Diamond homologs: A8X679, O43255, P21461, P29304, P61092, P61093, P93748, Q06985, Q06986, Q10L91, Q7SYL3, Q7ZVG6, Q84JL3, Q86MW9, Q8I147, Q8IUQ4, Q8IW03, Q8R4T2, Q8T3Y0, Q920M9, Q965X6, Q9FKD9, Q9I8X5, Q9M2P4, Q9STN8, Q84K34, Q8S3N1, Q9C6H2, Q9C6H4, Q9C9M0, Q9FKD5, Q9FKD6, Q9FKD7, Q9C6H3, Q9VZV5, Q6J2U6, Q9ET26, Q7XA77, Q9FM14

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
Ub:E2	“up-regulates activity”	SIAH3	ubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

64 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	55
Likely benign	5
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

792 predictions. Top by Δscore:

Variant	Effect	Δscore
13:45784054:CATA:C	acceptor_gain	1.0000
13:45784056:TA:T	acceptor_gain	1.0000
13:45784058:C:CC	acceptor_gain	1.0000
13:45851490:CTCA:C	donor_loss	1.0000
13:45851491:TCAC:T	donor_loss	1.0000
13:45851492:CAC:C	donor_loss	1.0000
13:45851493:ACC:A	donor_loss	1.0000
13:45851494:C:G	donor_loss	1.0000
13:45783315:T:TA	donor_gain	0.9900
13:45784053:ACATA:A	acceptor_gain	0.9900
13:45784054:CATAC:C	acceptor_gain	0.9900
13:45784055:ATA:A	acceptor_gain	0.9900
13:45784055:ATACT:A	acceptor_loss	0.9900
13:45784056:TACTG:T	acceptor_loss	0.9900
13:45784058:C:CG	acceptor_loss	0.9900
13:45825612:C:CT	acceptor_gain	0.9900
13:45851493:A:AC	donor_gain	0.9900
13:45851494:C:CC	donor_gain	0.9900
13:45782846:TTG:T	donor_gain	0.9700
13:45851494:CCT:C	donor_gain	0.9700
13:45851494:CCTTT:C	donor_gain	0.9700
13:45778739:A:T	acceptor_gain	0.9600
13:45851493:AC:A	donor_gain	0.9600
13:45851494:CC:C	donor_gain	0.9600
13:45851494:CCTT:C	donor_gain	0.9500
13:45784060:G:GC	acceptor_gain	0.9200
13:45783387:A:C	donor_gain	0.9100
13:45782843:G:C	donor_gain	0.9000
13:45784060:G:C	acceptor_gain	0.9000
13:45838952:T:TC	acceptor_gain	0.9000

AlphaMissense

1792 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:45783547:C:G	A216P	0.999
13:45783553:A:G	W214R	0.999
13:45783553:A:T	W214R	0.999
13:45783692:A:C	F167L	0.999
13:45783692:A:T	F167L	0.999
13:45783694:A:G	F167L	0.999
13:45783459:A:G	F245S	0.998
13:45783540:G:T	P218H	0.998
13:45783551:C:A	W214C	0.998
13:45783551:C:G	W214C	0.998
13:45783579:A:G	L205P	0.998
13:45783585:A:G	L203P	0.998
13:45783674:T:A	K173N	0.998
13:45783674:T:G	K173N	0.998
13:45783681:A:G	L171P	0.998
13:45783693:A:G	F167S	0.998
13:45783458:G:C	F245L	0.997
13:45783458:G:T	F245L	0.997
13:45783460:A:G	F245L	0.997
13:45783558:A:G	L212P	0.997
13:45783564:C:G	R210P	0.997
13:45783622:C:A	G191W	0.997
13:45783727:A:G	W156R	0.997
13:45783727:A:T	W156R	0.997
13:45783765:A:G	F143S	0.997
13:45783441:A:G	L251P	0.996
13:45783596:G:C	F199L	0.996
13:45783596:G:T	F199L	0.996
13:45783597:A:G	F199S	0.996
13:45783598:A:G	F199L	0.996

dbSNP variants (sampled 300 via entrez): RS1000007392 (13:45838447 T>G), RS1000055012 (13:45792588 C>T), RS1000076733 (13:45788692 A>G), RS1000081178 (13:45798279 C>A,T), RS1000101827 (13:45838199 A>C), RS1000139927 (13:45814095 C>A,T), RS1000162530 (13:45814713 A>C,G), RS1000182748 (13:45837137 T>G), RS1000194591 (13:45822761 C>A,T), RS1000230268 (13:45825029 A>C), RS1000298320 (13:45781143 C>A), RS1000321045 (13:45814447 G>A), RS1000337648 (13:45831396 G>T), RS1000444440 (13:45824774 G>T), RS1000444634 (13:45832106 G>A)

Disease associations

OMIM: gene MIM:615609 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST006491_2	Circulating fibroblast growth factor 23 levels	3.000000e-06
GCST009557_11	Rate of ventricular enlargement	4.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0010570	ventricular enlargement measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

10 total (human), top 10 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	2
sodium arsenite	increases expression	1
aflatoxin B2	increases methylation	1
perfluoro-n-nonanoic acid	increases expression	1
perfluorohexanesulfonic acid	increases expression	1
Benzo(a)pyrene	affects methylation, decreases methylation, increases methylation	1
Phthalic Acids	increases methylation	1
Tobacco Smoke Pollution	decreases expression	1
Vanadates	decreases expression	1
Aflatoxin B1	decreases methylation	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.