SAV1

Summary

SAV1 (salvador family WW domain containing protein 1, HGNC:17795) is a protein-coding gene on chromosome 14q22.1, encoding Protein salvador homolog 1 (Q9H4B6). Regulator of STK3/MST2 and STK4/MST1 in the Hippo signaling pathway which plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis.

WW domain-containing proteins are found in all eukaryotes and play an important role in the regulation of a wide variety of cellular functions such as protein degradation, transcription, and RNA splicing. This gene encodes a protein with two WW domains, a SARAH domain, and a coiled-coil region and is ubiquitously expressed in adult tissues. This protein binds to MST1 (mammalian sterile 20-like kinase 1) and promotes MST1-induced apoptosis. It has also been shown to bind to HAX1 (hematopoietic cell-specific protein 1 (HS1)-associated protein X-1) and to attenuate the anti-apoptotic effects of HAX1. Studies in human and mouse suggest this gene acts as a tumor suppressor.

Source: NCBI Gene 60485 — RefSeq curated summary.

At a glance

• GWAS associations: 18
• Clinical variants (ClinVar): 41 total
• Druggable target: yes
• MANE Select transcript: NM_021818

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17795
Approved symbol	SAV1
Name	salvador family WW domain containing protein 1
Location	14q22.1
Locus type	gene with protein product
Status	Approved
Aliases	WW45, WWP4, salvador
Ensembl gene	ENSG00000151748
Ensembl biotype	protein_coding
OMIM	607203
Entrez	60485

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 6 protein_coding, 1 retained_intron

ENST00000324679, ENST00000553731, ENST00000555720, ENST00000556735, ENST00000557458, ENST00000602664, ENST00000873683

RefSeq mRNA: 1 — MANE Select: NM_021818 NM_021818

CCDS: CCDS9701

Canonical transcript exons

ENST00000324679 — 5 exons

Exon	Start	End
ENSE00001001537	50640750	50640893
ENSE00001001539	50644744	50645014
ENSE00001246769	50665179	50665619
ENSE00001246821	50633580	50635384
ENSE00001246829	50667874	50668306

Expression profiles

Bgee: expression breadth ubiquitous, 278 present calls, max score 95.84.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 26.7688 / max 793.7133, expressed in 1808 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
143162	16.1542	1784
143163	9.0005	1759
143165	0.6889	330
143164	0.5312	280
143167	0.3084	84
143166	0.0857	42

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	95.84	gold quality
mucosa of paranasal sinus	UBERON:0005030	95.17	gold quality
secondary oocyte	CL:0000655	95.12	gold quality
nipple	UBERON:0002030	95.07	gold quality
mammary duct	UBERON:0001765	94.60	gold quality
epithelium of mammary gland	UBERON:0003244	94.21	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	94.21	gold quality
calcaneal tendon	UBERON:0003701	93.54	gold quality
urethra	UBERON:0000057	93.38	gold quality
body of pancreas	UBERON:0001150	93.30	gold quality
superficial temporal artery	UBERON:0001614	93.16	gold quality
gall bladder	UBERON:0002110	92.79	gold quality
pigmented layer of retina	UBERON:0001782	92.71	gold quality
parotid gland	UBERON:0001831	92.69	gold quality
mammary gland	UBERON:0001911	92.64	gold quality
thoracic mammary gland	UBERON:0005200	92.60	gold quality
tibial artery	UBERON:0007610	92.48	gold quality
popliteal artery	UBERON:0002250	92.47	gold quality
descending thoracic aorta	UBERON:0002345	92.38	gold quality
synovial joint	UBERON:0002217	92.37	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	92.36	gold quality
cardia of stomach	UBERON:0001162	92.31	gold quality
layer of synovial tissue	UBERON:0007616	92.16	gold quality
pericardium	UBERON:0002407	92.12	gold quality
lower lobe of lung	UBERON:0008949	92.08	gold quality
subcutaneous adipose tissue	UBERON:0002190	91.92	gold quality
aorta	UBERON:0000947	91.87	gold quality
pancreas	UBERON:0001264	91.84	gold quality
adipose tissue	UBERON:0001013	91.81	gold quality
renal medulla	UBERON:0000362	91.72	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	11.69

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

105 targeting SAV1, 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-1277-5P	100.00	73.95	5056
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-548AT-5P	99.96	70.83	2666

Literature-anchored findings (GeneRIF, showing 24)

• Salvador gene is not frequently mutated in human carcinoma tissues. (PMID:12969014)
• Together these results show that hSav can bind to, and be phosphorylated by, Mst, and that the stabilizing effect of Mst on hSav requires its interaction with hSav but is probably not due to phosphorylation of hSav by Mst. (PMID:16930133)
• hWW45 is required to enhance MST1-mediated apoptosis in vivo and thus is a critical player in an MST1-driven cell death signaling pathway. (PMID:19212654)
• hSav1 is a newly identified protein that interacts with Mst1 and augments Mst1-mediated apoptosis. (PMID:19950692)
• Study reports that two Hippo pathway components, Mst2 and the scaffold protein hSav1, directly interact with Nek2A and regulate its ability to localize to centrosomes, and phosphorylate C-Nap1 and rootletin. (PMID:21076410)
• MST and hSAV act as novel co-regulators of ERalpha and may play an important role in breast cancer pathogenesis. (PMID:21104395)
• a role for Salvador as a human tumor suppressor and RASSF1A effector and show that Salvador allows RASSF1A to modulate p73 independently of the hippo pathway. (PMID:21489991)
• hSav1 interacts with HAX1 and attenuates its protective role against apoptosis in MCF-7 breast cancer cells. (PMID:21567072)
• downregulation of SAV1 and the consequent YAP1 activation are involved in the pathogenesis of high-grade clear cell renal cell carcinoma. (PMID:22185343)
• We also confirmed the interaction of HAX-1 and hSav1 in mammalian cells. (PMID:22570112)
• Mst2 and the Ser-3 residue of human WW45 function independently of each other in the regulation of the stability of human WW45. (PMID:23524264)
• MST1/2-SAV1 associates with the NPHP transition-zone complex, promoting ciliary localization of multiple ciliary cargoes. (PMID:25367221)
• using an Mst2 mutation that disrupts homotypic dimerization, we showed that the monomeric Mst2-SARAH domain could form a stable complex of 1:1 stoichiometric ratio with WW45 refolded under acidic pH. (PMID:25814670)
• WW45 has suppressive roles in lung cancer through a pathway involving Hedgehog/Gli1 signaling. (PMID:27661123)
• SAV1 represses the activation of the Akt-mTOR signalling, and rapamycin treatment blunts the effects of SAV1 on in vitro and in vivo growth of colorectal cancer cells. (PMID:28618450)
• Here, the authors discover SAV1-mediated inhibition of the PP2A complex STRIPAK(SLMAP) as a key mechanism of MST1/2 activation. (PMID:29063833)
• These results suggest Salvador enhances the effects of Hippo kinase activity at multiple points in the Hippo pathway. (PMID:29519817)
• SAV1 suppresses tumor growth in colorectal cancer and is regulated by miR-21. (PMID:30681889)
• BCL-2 is a new regulator of MST pathway. First, protein levels of MST2 and SAV1 were reduced significantly by co-expression of BCL-2. Physical interaction of BCL-2 with SAV1 was correlated with proteasomal degradation of SAV1 and MST2 proteins. (PMID:30867124)
• Authors report that SAV1, a Hippo signaling component, inhibits Akt, a function independent of its role in Hippo signaling. Binding to a proline-tyrosine motif in the Akt-PH domain, SAV1 suppresses Akt activation by blocking Akt’s movement to plasma membrane. Authors further identify cancer-associated SAV1 mutations with impaired ability to bind Akt, leading to Akt hyperactivation. (PMID:30944303)
• RNA-binding protein Musashi2 regulates Hippo signaling via SAV1 and MOB1 in pancreatic cancer. (PMID:32780197)
• Cell adhesion molecule KIRREL1 is a feedback regulator of Hippo signaling recruiting SAV1 to cell-cell contact sites. (PMID:35177623)
• ALKBH5 Promotes Multiple Myeloma Tumorigenicity through inducing m(6)A-demethylation of SAV1 mRNA and Myeloma Stem Cell Phenotype. (PMID:35414790)
• Smoke-induced SAV1 Gene Promoter Hypermethylation Disrupts YAP Negative Feedback and Promotes Malignant Progression of Non-small Cell Lung Cancer. (PMID:35864957)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	sav1	ENSDARG00000006196
mus_musculus	Sav1	ENSMUSG00000021067
rattus_norvegicus	Sav1	ENSRNOG00000005264
drosophila_melanogaster	sav	FBGN0053193
caenorhabditis_elegans		WBGENE00020427

Paralogs (6): MAGI3 (ENSG00000081026), GRIP2 (ENSG00000144596), MAGI1 (ENSG00000151276), GRIP1 (ENSG00000155974), MAGI2 (ENSG00000187391), MAGIX (ENSG00000269313)

Protein

Protein identifiers

Protein salvador homolog 1 — Q9H4B6 (reviewed: Q9H4B6)

Alternative names: 45 kDa WW domain protein

All UniProt accessions (5): Q9H4B6, G3V453, H0YJ02, H0YJH0, H0YJT4

UniProt curated annotations — full annotation on UniProt →

Function. Regulator of STK3/MST2 and STK4/MST1 in the Hippo signaling pathway which plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein STK3/MST2 and STK4/MST1, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. Phosphorylation of YAP1 by LATS1/2 inhibits its translocation into the nucleus to regulate cellular genes important for cell proliferation, cell death, and cell migration. SAV1 is required for STK3/MST2 and STK4/MST1 activation and promotes cell-cycle exit and terminal differentiation in developing epithelial tissues. Plays a role in centrosome disjunction by regulating the localization of NEK2 to centrosomes, and its ability to phosphorylate CROCC and CEP250. In conjunction with STK3/MST2, activates the transcriptional activity of ESR1 through the modulation of its phosphorylation.

Subunit / interactions. Homodimer. Stabilized through interaction with STK3/MST2 or STK4/MST1. Interacts (via SARAH domain) with isoform 1 of NEK2. Interacts with ESR1 only in the presence of STK3/MST2. Interacts with WTIP and AJUBA.

Subcellular location. Nucleus. Cytoplasm.

Tissue specificity. Ubiquitously expressed in adult tissues with highest expression in the pancreas, aorta and interventricular septum and lowest expression in skeletal muscle. Expression was higher in fetal than in the adult heart. Expressed in various cell lines.

Post-translational modifications. Phosphorylated by STK3/MST2 and STK4/MST1. Phosphorylation is not required for SAV1 stability and may increase the number of protein binding sites on the scaffold molecule.

RefSeq proteins (1): NP_068590* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001202	WW_dom	Domain
IPR011524	SARAH_dom	Domain
IPR030030	Sav	Family
IPR036020	WW_dom_sf	Homologous_superfamily

Pfam: PF00397

UniProt features (23 total): mutagenesis site 7, domain 3, sequence conflict 3, helix 3, modified residue 3, chain 1, strand 1, coiled-coil region 1, sequence variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6AO5	X-RAY DIFFRACTION	2.96

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H4B6-F1	60.52	0.21

Functional residue map

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

Post-translational modifications (3): 94, 136, 210

Mutagenesis-validated functional residues (7):

Position	Phenotype
350	loss of interaction with stk3.
357	loss of interaction with stk3.
358	loss of interaction with stk3.
361	loss of interaction with stk3.
365	loss of interaction with stk3.
368	loss of interaction with stk3.
346	loss of interaction with stk3.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-2028269	Signaling by Hippo
R-HSA-162582	Signal Transduction

MSigDB gene sets: 287 (showing top): GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_EPITHELIAL_CELL_PROLIFERATION, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_FAT_CELL_DIFFERENTIATION, GOBP_LUNG_EPITHELIUM_DEVELOPMENT, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_CARDIAC_SEPTUM_DEVELOPMENT, GOBP_VENTRICULAR_SEPTUM_MORPHOGENESIS, BERTUCCI_MEDULLARY_VS_DUCTAL_BREAST_CANCER_DN, MODULE_255, GOBP_CARDIAC_CHAMBER_MORPHOGENESIS, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, GOBP_LUNG_CELL_DIFFERENTIATION, GOBP_POSITIVE_REGULATION_OF_FAT_CELL_DIFFERENTIATION, GOBP_GROWTH

GO Biological Process (24): hair follicle development (GO:0001942), negative regulation of cell population proliferation (GO:0008285), keratinocyte differentiation (GO:0030216), hippo signaling (GO:0035329), positive regulation of apoptotic process (GO:0043065), positive regulation of fat cell differentiation (GO:0045600), epithelial cell proliferation (GO:0050673), negative regulation of epithelial cell proliferation (GO:0050680), protein stabilization (GO:0050821), cardiac muscle cell proliferation (GO:0060038), negative regulation of cardiac muscle cell proliferation (GO:0060044), ventricular septum morphogenesis (GO:0060412), lung epithelial cell differentiation (GO:0060487), intestinal epithelial cell differentiation (GO:0060575), keratinocyte apoptotic process (GO:0097283), positive regulation of keratinocyte apoptotic process (GO:1902174), regulation of stem cell population maintenance (GO:2000036), apoptotic process (GO:0006915), signal transduction (GO:0007165), regulation of gene expression (GO:0010468), negative regulation of hippo signaling (GO:0035331), positive regulation of hippo signaling (GO:0035332), regulation of cell population proliferation (GO:0042127), regulation of organ growth (GO:0046620)

GO Molecular Function (5): identical protein binding (GO:0042802), protein serine/threonine kinase activator activity (GO:0043539), molecular adaptor activity (GO:0060090), transcription regulator activator activity (GO:0140537), protein binding (GO:0005515)

GO Cellular Component (3): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell population proliferation	2
negative regulation of cell population proliferation	2
binding	2
cellular anatomical structure	2
hair cycle process	1
anatomical structure development	1
skin epidermis development	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
epidermal cell differentiation	1
skin development	1
intracellular signal transduction	1
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
fat cell differentiation	1
positive regulation of cell differentiation	1
regulation of fat cell differentiation	1
epithelial cell proliferation	1
regulation of epithelial cell proliferation	1
regulation of protein stability	1
striated muscle cell proliferation	1
cardiac muscle tissue growth	1
negative regulation of cardiac muscle tissue growth	1
cardiac muscle cell proliferation	1
regulation of cardiac muscle cell proliferation	1
ventricular septum development	1
cardiac septum morphogenesis	1
epithelial cell differentiation	1
lung epithelium development	1
lung cell differentiation	1
columnar/cuboidal epithelial cell differentiation	1
digestive tract development	1
epithelial cell apoptotic process	1
keratinocyte apoptotic process	1
regulation of keratinocyte apoptotic process	1
positive regulation of epithelial cell apoptotic process	1
stem cell population maintenance	1
regulation of developmental process	1
regulation of multicellular organismal process	1

Protein interactions and networks

STRING

984 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SAV1	LATS1	O95835	998
SAV1	STK4	Q13043	995
SAV1	GFER	P55789	990
SAV1	LATS2	Q9NRM7	979
SAV1	NF2	P35240	931
SAV1	MOB1A	Q9H8S9	918
SAV1	STK24	Q9Y6E0	885
SAV1	RASSF1	Q9NS23	868
SAV1	DIAPH1	O60610	862
SAV1	MOB1B	Q7L9L4	860
SAV1	WWC1	Q8IX03	838
SAV1	MST1	P26927	818
SAV1	YAP1	P46937	813
SAV1	TEAD1	P28347	803
SAV1	WWTR1	Q9GZV5	789

IntAct

182 interactions, top by confidence:

A	B	Type	Score
STK3	SAV1	psi-mi:“MI:0915”(physical association)	0.960
SAV1	STK3	psi-mi:“MI:0217”(phosphorylation reaction)	0.960
SAV1	STK3	psi-mi:“MI:0915”(physical association)	0.960
STK3	RASSF2	psi-mi:“MI:0914”(association)	0.950
SAV1	STK4	psi-mi:“MI:0915”(physical association)	0.940
STK4	SAV1	psi-mi:“MI:0915”(physical association)	0.940
SAV1	STK4	psi-mi:“MI:0914”(association)	0.940
STK4	RASSF2	psi-mi:“MI:0914”(association)	0.930
HAX1	SAV1	psi-mi:“MI:0915”(physical association)	0.740
SAV1	HAX1	psi-mi:“MI:0403”(colocalization)	0.740
STK4	MAP1B	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710

BioGRID (248): SAV1 (Affinity Capture-MS), SAV1 (Affinity Capture-MS), STK3 (Affinity Capture-MS), STK4 (Affinity Capture-MS), GRN (Affinity Capture-MS), YTHDF1 (Affinity Capture-MS), BAG1 (Affinity Capture-MS), SEMG1 (Affinity Capture-MS), SAV1 (Affinity Capture-MS), SAV1 (Affinity Capture-MS), AJUBA (Affinity Capture-Western), WTIP (Affinity Capture-Western), SAV1 (Affinity Capture-MS), SAV1 (Affinity Capture-MS), STK4 (Affinity Capture-MS)

ESM2 similar proteins: A0A1L8H8C0, A0A1L8HFX9, A2CEX1, A2RUV4, A4V8B4, A8XU52, C5DGS4, C5DT56, E7KIY3, E9QDC5, F1QPR4, G5EEK3, H2L045, O60504, P27715, Q02645, Q02831, Q11181, Q32NM7, Q3U5C7, Q571K4, Q5T5U3, Q5U303, Q60JJ0, Q6DFG0, Q6DFV3, Q71H61, Q71M21, Q71QF9, Q7Z3G6, Q7ZXH3, Q80Y24, Q86SQ0, Q8BRG8, Q8K1N2, Q8N5C8, Q8NEY8, Q8VEB2, Q96MT3, Q96SK2

Diamond homologs: A1CQG2, A1D3C5, A2QQ28, A4V8B4, B0XQ72, B8N7E5, D6C652, G0S9J5, H2LBU8, P46934, P46935, Q0CCL1, Q1L8J7, Q2UBP1, Q4WTF3, Q5BDP1, Q62940, Q7XZU0, Q8VEB2, Q92462, Q9H4B6, Q9HCE7, Q9VCR6, Q9VVI3, Q9Y0H4, A0A8C0NGY6, A0A8I3PQN6, A1A5G4, A4IIJ3, B3LWS4, B3P3M8, B4HEJ6, B4K6I9, B4M5X4, B4NAD3, B4PSQ2, O14326, O88382, O95817, P39940

SIGNOR signaling

10 interactions.

A	Effect	B	Mechanism
SAV1	up-regulates	STK3	binding
SAV1	up-regulates	STK4	binding
SAV1	“up-regulates activity”	STK3/4	binding
STK3/4	“up-regulates activity”	SAV1	phosphorylation
SAV1	“up-regulates quantity by stabilization”	STK3	binding
SAV1	“up-regulates quantity by stabilization”	STK4	binding
STK25	“down-regulates activity”	SAV1	phosphorylation
STK4	up-regulates	SAV1
STK3	up-regulates	SAV1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 173 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Signaling by Hippo	6	29.1×	2e-05

GO biological processes:

GO term	Partners	Fold	FDR
hippo signaling	6	28.9×	4e-05
protein stabilization	12	5.3×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	36
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1269 predictions. Top by Δscore:

Variant	Effect	Δscore
14:50632225:CTA:C	acceptor_loss	1.0000
14:50632226:TA:T	acceptor_loss	1.0000
14:50632227:A:AG	acceptor_gain	1.0000
14:50632227:A:AT	acceptor_loss	1.0000
14:50632228:G:GG	acceptor_gain	1.0000
14:50635380:CATAT:C	acceptor_gain	1.0000
14:50635382:TAT:T	acceptor_gain	1.0000
14:50635384:TC:T	acceptor_loss	1.0000
14:50635385:C:CC	acceptor_gain	1.0000
14:50635385:C:T	acceptor_loss	1.0000
14:50635386:T:C	acceptor_loss	1.0000
14:50640744:ACTT:A	donor_loss	1.0000
14:50640745:CTT:C	donor_loss	1.0000
14:50640746:TTA:T	donor_loss	1.0000
14:50640748:A:AC	donor_gain	1.0000
14:50640748:ACTT:A	donor_gain	1.0000
14:50640749:C:CT	donor_gain	1.0000
14:50640749:CT:C	donor_gain	1.0000
14:50640749:CTT:C	donor_gain	1.0000
14:50640749:CTTC:C	donor_gain	1.0000
14:50640749:CTTCA:C	donor_gain	1.0000
14:50640890:TACA:T	acceptor_gain	1.0000
14:50640891:ACA:A	acceptor_gain	1.0000
14:50640892:CA:C	acceptor_gain	1.0000
14:50640892:CAC:C	acceptor_gain	1.0000
14:50640892:CACT:C	acceptor_loss	1.0000
14:50640894:C:CC	acceptor_gain	1.0000
14:50640894:CT:C	acceptor_loss	1.0000
14:50640895:T:A	acceptor_loss	1.0000
14:50644822:A:C	donor_gain	1.0000

AlphaMissense

2485 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:50635253:A:G	L361P	1.000
14:50635283:A:T	V351D	1.000
14:50635310:A:G	L342P	1.000
14:50635319:A:G	L339P	1.000
14:50635340:A:G	L332P	1.000
14:50635354:G:C	F327L	1.000
14:50635354:G:T	F327L	1.000
14:50635355:A:G	F327S	1.000
14:50635356:A:G	F327L	1.000
14:50635363:C:A	W324C	1.000
14:50635363:C:G	W324C	1.000
14:50635364:C:G	W324S	1.000
14:50635365:A:G	W324R	1.000
14:50635365:A:T	W324R	1.000
14:50635370:A:G	L322P	1.000
14:50635379:T:A	D319V	1.000
14:50640769:A:C	Y311D	1.000
14:50640777:A:G	L308P	1.000
14:50640777:A:T	L308H	1.000
14:50640779:C:A	W307C	1.000
14:50640779:C:G	W307C	1.000
14:50640780:C:G	W307S	1.000
14:50640781:A:G	W307R	1.000
14:50640781:A:T	W307R	1.000
14:50644799:A:C	Y251D	1.000
14:50644830:C:A	W240C	1.000
14:50644830:C:G	W240C	1.000
14:50644832:A:G	W240R	1.000
14:50644832:A:T	W240R	1.000
14:50644869:C:A	W227C	1.000

dbSNP variants (sampled 300 via entrez): RS1000026653 (14:50668750 G>A,T), RS1000262128 (14:50648436 A>C,G), RS1000349765 (14:50664554 G>A), RS1000421179 (14:50646797 A>T), RS1000535205 (14:50643427 G>C,T), RS1000538009 (14:50668473 C>G), RS1000584642 (14:50637191 C>G), RS1000614343 (14:50635735 G>A), RS1000712428 (14:50641724 T>C,G), RS1000800427 (14:50652149 G>C), RS1000913978 (14:50656503 C>T), RS1001026520 (14:50668401 C>A), RS1001142679 (14:50661808 C>T), RS1001305477 (14:50662884 G>C), RS1001336618 (14:50650752 T>C)

Disease associations

OMIM: gene MIM:607203 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): hereditary breast ovarian cancer syndrome (MONDO:0003582)

Orphanet (1): Hereditary breast and/or ovarian cancer syndrome (Orphanet:145)

HPO phenotypes

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

GWAS associations

18 associations (top):

Study	Trait	p-value
GCST002312_10	Periodontal disease-related phenotype (Socransky)	8.000000e-06
GCST002360_1	Plasma amyloid beta peptide concentrations (ABx-40)	8.000000e-07
GCST002479_13	Lupus nephritis in systemic lupus erythematosus	3.000000e-07
GCST004599_162	Mean platelet volume	6.000000e-18
GCST004858_18	Dupuytren’s disease	2.000000e-17
GCST006979_1045	Heel bone mineral density	4.000000e-11
GCST007294_112	Body fat distribution (trunk fat ratio)	3.000000e-08
GCST007294_152	Body fat distribution (trunk fat ratio)	1.000000e-12
GCST007294_92	Body fat distribution (trunk fat ratio)	8.000000e-06
GCST007295_114	Body fat distribution (leg fat ratio)	3.000000e-08
GCST007295_16	Body fat distribution (leg fat ratio)	1.000000e-11
GCST007295_96	Body fat distribution (leg fat ratio)	2.000000e-18
GCST010002_150	Refractive error	1.000000e-11
GCST90002395_169	Mean platelet volume	4.000000e-41
GCST90002395_170	Mean platelet volume	1.000000e-29
GCST90002401_72	Platelet distribution width	2.000000e-14
GCST90002402_229	Platelet count	6.000000e-13
GCST90002402_230	Platelet count	3.000000e-12

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0005659	plasma beta-amyloid 1-40 measurement
EFO:0004229	Dupuytren Contracture
EFO:0009270	heel bone mineral density
EFO:0004341	body fat distribution
EFO:0007984	platelet component distribution width
EFO:0004309	platelet count

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D061325	Hereditary Breast and Ovarian Cancer Syndrome	C04.588.180.483; C04.588.322.455.431; C04.700.517; C12.050.351.500.056.630.705.431; C12.050.351.937.418.685.431; C12.100.250.056.630.705.431; C12.900.418.685.431; C16.320.700.517; C17.800.090.500.483; C19.344.410.431; C19.391.630.705.431

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067345 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 4 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.51	Kd	308.6	nM	CHEMBL5653589
6.45	ED50	356	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 4 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149345: Binding affinity to human SAV1 incubated for 45 mins by Kinobead based pull down assay	kd	0.3085	uM

CTD chemical–gene interactions

33 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases expression	2
sodium arsenite	increases abundance, increases expression, decreases expression	2
Nickel	increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression, increases expression	2
FR900359	decreases phosphorylation	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
cobaltous chloride	increases expression	1
nickel chloride	increases expression	1
periodate-oxidized adenosine	affects expression	1
evodiamine	increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
torcetrapib	increases expression	1
abrine	increases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	increases expression, increases response to substance	1
Sunitinib	increases expression	1
Zoledronic Acid	increases expression	1
Arsenic Trioxide	increases expression	1
Acetaminophen	increases expression	1
Arsenic	increases abundance, decreases expression	1
Cadmium	increases abundance, increases expression	1
Cisplatin	increases expression, affects cotreatment	1
Piroxicam	affects cotreatment, increases expression	1
Smoke	decreases expression	1
Thimerosal	decreases expression	1
Thiram	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Urethane	increases expression	1
Valproic Acid	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652387	Binding	Binding affinity to human SAV1 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

8 cell lines: 8 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_5185	Y-MESO-28	Cancer cell line	Male
CVCL_B9RI	Abcam A-549 SAV1 KO	Cancer cell line	Male
CVCL_D6UU	786-O SAV1 clone 1	Cancer cell line	Male
CVCL_D6UV	786-O SAV1 clone 2	Cancer cell line	Male
CVCL_TK06	HAP1 SAV1 (-) 1	Cancer cell line	Male
CVCL_XS44	HAP1 SAV1 (-) 2	Cancer cell line	Male
CVCL_XS45	HAP1 SAV1 (-) 3	Cancer cell line	Male
CVCL_XS46	HAP1 SAV1 (-) 4	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02562170	PHASE4	COMPLETED	Protexa® Versus TiLoopBra® in Immediate Breast Reconstruction- A Pilot Study
NCT00673335	PHASE3	COMPLETED	Letrozole in Preventing Breast Cancer in Postmenopausal Women With a BRCA1 or BRCA2 Mutation
NCT00685256	PHASE3	COMPLETED	Standard Genetic Counseling With or Without a Decision Guide in Improving Communication Between Mothers Undergoing BRCA1/2 Testing and Their Minor-Age Children
NCT03162276	PHASE3	UNKNOWN	Trial of Inquiry Based Stress Reduction (IBSR) Program for BRCA1/2 Mutation Carriers
NCT00253539	PHASE2	COMPLETED	Arzoxifene or Tamoxifen in Preventing Breast Cancer in Premenopausal Women at High Risk for Breast Cancer
NCT00305695	PHASE2	COMPLETED	Zoledronate or Observation in Maintaining Bone Mineral Density in Patients Who Are Undergoing Surgery to Remove Both Ovaries
NCT00321633	PHASE2	COMPLETED	Carboplatin or Docetaxel in Treating Women With Metastatic Genetic Breast Cancer
NCT01333748	PHASE2	COMPLETED	Search Allelic Imbalance of Expression of BRCA Genes in Hereditary Risk of Breast and/or Ovarian Cancer
NCT01367639	PHASE2	COMPLETED	Trial of Inquiry Based Stress Reduction (IBSR) Program for BRCA1/2 Mutation Carriers
NCT00535119	PHASE1	COMPLETED	Veliparib, Carboplatin, and Paclitaxel in Treating Patients With Advanced Solid Cancer
NCT00892736	PHASE1	COMPLETED	Veliparib in Treating Patients With Malignant Solid Tumors That Do Not Respond to Previous Therapy
NCT03832985	EARLY_PHASE1	COMPLETED	Pediatric Reporting of Adult-Onset Genomic Results
NCT00005095	Not specified	RECRUITING	Specimen and Data Study for Ovarian Cancer Early Detection and Prevention
NCT00609505	Not specified	COMPLETED	Telemedicine vs. Face-to-Face Cancer Genetic Counseling
NCT01273909	Not specified	UNKNOWN	Outcomes After Perforator Flap Reconstruction for Breast Reconstruction and/or Lymphedema Treatment
NCT01445275	Not specified	WITHDRAWN	Cost of Cancer Risk Management in Women at Elevated Genetic Risk for Ovarian Cancer Who Participated on GOG-0199
NCT01608074	Not specified	ACTIVE_NOT_RECRUITING	Radical Fimbriectomy for Young BRCA Mutation Carriers
NCT02087592	Not specified	COMPLETED	Feasibility of Lifestyle Intervention in BRCA1/2 Mutation Carriers
NCT02302742	Not specified	RECRUITING	Triple Negative Breast Cancer and Germline Hereditary Breast and Ovarian Cancer Mutation Carrier Registry
NCT02324062	Not specified	COMPLETED	Cancer Genetics Hereditary Cancer Panel Testing
NCT02516540	Not specified	UNKNOWN	Efficacy of Lifestyle Intervention in BRCA1/2 Mutation Carriers
NCT02653105	Not specified	ACTIVE_NOT_RECRUITING	Women at Risk of Breast Cancer and OLFM4
NCT02705924	Not specified	TERMINATED	Impact of a Psychoeducational Intervention on Expectations and Coping in Young Women Exposed to a High HBOC Risk
NCT02760849	Not specified	ACTIVE_NOT_RECRUITING	Surgery in Preventing Ovarian Cancer in Patients With Genetic Mutations
NCT02786147	Not specified	COMPLETED	Identification and Referral of Women at Risk for Hereditary Breast/Ovarian Cancer
NCT02956681	Not specified	COMPLETED	Statewide Communication to Reach Diverse Low Income Women
NCT03015376	Not specified	UNKNOWN	Inherited Susceptible Genes Among Epithelial Ovarian Cancer
NCT03050268	Not specified	RECRUITING	Familial Investigations of Childhood Cancer Predisposition
NCT03075540	Not specified	COMPLETED	Enhancing At-risk Latina Women’s Use of Genetic Counseling for Hereditary Breast and Ovarian Cancer
NCT03124212	Not specified	RECRUITING	Cascade Genetic Testing for Hereditary Breast/Ovarian Cancer and Lynch Syndrome in Switzerland
NCT03246841	Not specified	ACTIVE_NOT_RECRUITING	Investigation of Tumour Spectrum of Germline Mutations in Breast and Ovarian Cancer Genes.
NCT03294343	Not specified	UNKNOWN	Risk-Reducing Surgeries for Hereditary Ovarian Cancer
NCT03421327	Not specified	COMPLETED	Genetic Risk: Whether, When, and How to Tell Adolescents
NCT03510689	Not specified	COMPLETED	Genetics and Heart Health After Cancer Therapy
NCT03511690	Not specified	COMPLETED	Testing an Intelligent Tutoring System to Enhance Genetic Risk Assessment
NCT03784859	Not specified	COMPLETED	Tissue Expansion in Breast Reconstruction Without Drains
NCT03979612	Not specified	UNKNOWN	Evaluation of the Adhesion to the GENEPY Network
NCT04197856	Not specified	ACTIVE_NOT_RECRUITING	Direct Information to At-risk Relatives
NCT04407611	Not specified	COMPLETED	Scalable Communication Modalities for Returning Genetic Research Results
NCT04508764	Not specified	TERMINATED	Implementation of the Families Accelerating Cascade Testing Toolkit (FACTT) for Hereditary Breast and Ovarian Cancer and Lynch Syndrome