SRI

Summary

SRI (sorcin, HGNC:11292) is a protein-coding gene on chromosome 7q21.12, encoding Sorcin (P30626). Calcium-binding protein that modulates excitation-contraction coupling in the heart.

This gene encodes a calcium-binding protein with multiple E-F hand domains that relocates from the cytoplasm to the sarcoplasmic reticulum in response to elevated calcium levels. In addition to regulating intracellular calcium homeostasis it also modulates excitation-contraction coupling in the heart. Alternative splicing results in multiple transcript variants encoding distinct proteins. Multiple pseudogenes exist for this gene.

Source: NCBI Gene 6717 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hypertrophic cardiomyopathy (Refuted Evidence, GenCC)
• Clinical variants (ClinVar): 54 total — 1 pathogenic
• Druggable target: yes
• MANE Select transcript: NM_003130

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11292
Approved symbol	SRI
Name	sorcin
Location	7q21.12
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000075142
Ensembl biotype	protein_coding
OMIM	182520
Entrez	6717

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 11 protein_coding, 4 retained_intron, 1 nonsense_mediated_decay

ENST00000265729, ENST00000394641, ENST00000419179, ENST00000431660, ENST00000457606, ENST00000472930, ENST00000486860, ENST00000488015, ENST00000489079, ENST00000490437, ENST00000879559, ENST00000879560, ENST00000879561, ENST00000936810, ENST00000936811, ENST00000936812

RefSeq mRNA: 4 — MANE Select: NM_003130 NM_001256891, NM_001256892, NM_003130, NM_198901

CCDS: CCDS47638, CCDS5612, CCDS59063

Canonical transcript exons

ENST00000265729 — 8 exons

Exon	Start	End
ENSE00000877269	88219976	88220038
ENSE00001811340	88205115	88206504
ENSE00003484015	88209339	88209452
ENSE00003507076	88209983	88210130
ENSE00003579551	88217122	88217191
ENSE00003609519	88208507	88208565
ENSE00003625055	88210882	88210925
ENSE00003677181	88218859	88218942

Expression profiles

Bgee: expression breadth ubiquitous, 301 present calls, max score 99.85.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 81.9222 / max 486.9751, expressed in 1824 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
84742	80.3133	1824
84743	1.3182	133
84744	0.1662	39
84739	0.0771	23
84740	0.0474	24

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	99.85	gold quality
colonic mucosa	UBERON:0000317	99.74	gold quality
mucosa of sigmoid colon	UBERON:0004993	99.71	gold quality
rectum	UBERON:0001052	99.50	gold quality
bronchial epithelial cell	CL:0002328	99.44	gold quality
ileal mucosa	UBERON:0000331	99.34	gold quality
ventricular zone	UBERON:0003053	99.25	gold quality
oocyte	CL:0000023	99.10	gold quality
epithelium of bronchus	UBERON:0002031	99.01	gold quality
transverse colon	UBERON:0001157	98.95	gold quality
bronchus	UBERON:0002185	98.94	gold quality
secondary oocyte	CL:0000655	98.90	gold quality
right uterine tube	UBERON:0001302	98.81	gold quality
nucleus accumbens	UBERON:0001882	98.77	gold quality
ganglionic eminence	UBERON:0004023	98.75	gold quality
duodenum	UBERON:0002114	98.72	gold quality
caudate nucleus	UBERON:0001873	98.58	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	98.57	gold quality
anterior cingulate cortex	UBERON:0009835	98.56	gold quality
cingulate cortex	UBERON:0003027	98.55	gold quality
small intestine Peyer’s patch	UBERON:0003454	98.48	gold quality
amygdala	UBERON:0001876	98.44	gold quality
spinal cord	UBERON:0002240	98.37	gold quality
right frontal lobe	UBERON:0002810	98.34	gold quality
medial globus pallidus	UBERON:0002477	98.33	gold quality
large intestine	UBERON:0000059	98.31	gold quality
jejunal mucosa	UBERON:0000399	98.30	gold quality
intestine	UBERON:0000160	98.28	gold quality
hypothalamus	UBERON:0001898	98.27	gold quality
prefrontal cortex	UBERON:0000451	98.26	gold quality

Single-cell (SCXA)

Detected in 14 experiment(s), a significant marker in 13.

Experiment	Marker?	Max mean expression
E-MTAB-6701	yes	1878.78
E-HCAD-4	yes	141.46
E-HCAD-5	yes	35.21
E-GEOD-84465	yes	33.71
E-HCAD-1	yes	29.47
E-HCAD-13	yes	24.53
E-MTAB-9067	yes	20.94
E-MTAB-8410	yes	20.10
E-CURD-46	yes	12.37
E-GEOD-130148	yes	11.22
E-CURD-112	yes	10.46
E-GEOD-93593	yes	6.42
E-GEOD-125970	no	18.89
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

98 targeting SRI, 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-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488

Literature-anchored findings (GeneRIF, showing 38)

• relationship between soluble resistance-related calcium-binding protein (sorcin) gene and multidrug resistance gene (mdr1), and their significance in clinical drug resistance and prognosis of acute myeloid leukemia (AML) (PMID:12408767)
• Sorcin gene overexpression is significantly associated with clinical multidrug resistance and prognosis, it is one of the indicators for predicting prognosis of acute myeloid leukemia patients (PMID:12411058)
• data indicate that sorcin modulates intracellular calcium cycling and calcium influx pathways in the heart (PMID:12754254)
• SRI interacts with GCA in vivo and in vitro. (PMID:12804766)
• Overexpression of SOR improves cardiac contractility independent of beta-adrenergic stimulation. (PMID:15808837)
• Semi-quantitative RT-PCR experiments with 6 of those genes confirmed higher expression of DNCH2, ARHGEF6, NPM1 and SRI and lower expression of NRGN and TM4SF2 in GBM tumors. (PMID:16320026)
• Sorcin interacts with and modulates ryanodine receptor activity in rat vascular smooth muscle cells. (PMID:16931553)
• sorcin plays an important role in the emergence of MDR in leukemia cells via regulating cell apoptosis pathways (PMID:16934756)
• Knock-down of SRI induces up-regulation of MDR1 in HeLa cells. (PMID:17541155)
• provide a plausible structural and functional framework that helps elucidate the phenotypic alterations of mice overexpressing F112L-sorcin (PMID:17699613)
• Tetrandrine reverses multidrug-resistance of K562/A02 cells through regulation of expression of SORCIN. (PMID:18315902)
• Overexpression of sorcin could induce low level of multidrug resistant (MDR) in SGC7901 cells, indicating that sorcin is associated with MDR of SGC7901 cells. (PMID:18423116)
• Upregulation of sorcin is associated with gastric cancer. (PMID:19885748)
• Overexpression of sorcin was associated with gemcitabine resistance in non-small cell lung cancer. (PMID:20012234)
• Depletion of TRAP1 by short hairpin RNA in colorectal carcinoma cells lowered Sorcin levels in mitochondria, whereas the depletion of Sorcin by small interfering RNA increased TRAP1 degradation. (PMID:20647321)
• The study indicates that stomatin, sorcin, and synexin are echinophilic membrane components that mainly locate outside GM1 rafts in the human erythrocyte membrane. (PMID:20858460)
• Overexpression of sorcin by gene transfection was able to confer drug resistance in gastric cancer cells (PMID:21109982)
• Data show that colorectal cancer cells overexpress sorcin as an adaptive mechanism to prevent endoplasmic reticulum stress and escape apoptosis triggered by chemotherapeutic agents. (PMID:22052463)
• sorcin retains ChREBP in the cytosol at low glucose concentrations and may act as a Ca(2+) sensor for glucose-induced nuclear translocation and the activation of ChREBP-dependent genes. (PMID:22338092)
• The role of sorcin in multidrug resistance in cancer. [Review] (PMID:22701893)
• down-regulation of sorcin did not alter expression or function of P-gp, but induced cell apoptosis and chemosensitivity in K562/ A02 and MCF-7/A02 (PMID:24013575)
• sorcin regulates epithelial-mesenchymal transition and cancer stem cells partly through E-cadherin and vascular endothelial growth factor expression. (PMID:24337682)
• Key cellular signaling pathways were triggered by sorcin silencing in the drug resistance of human nasopharyngeal carcinoma. (PMID:24376145)
• Sorcin links calcium signaling to vesicle trafficking, regulates Polo-like kinase 1 and is necessary for mitosis. (PMID:24427308)
• overexpression of sorcin increased the phosphorylation of CREB1 and the binding of CREB1 to the CRE sequence of mdr1/p-gp promoter, and induced the expression of MDR1/P-gp (PMID:24796664)
• Sorcin antibody as a possible predictive factor in conversion from radiologically isolated syndrome to multiple sclerosis: a preliminary study (PMID:25001342)
• Sorcin is highly expressed in the heart and in the brain, and overexpressed in many cancer cells. [Review] (PMID:25197934)
• Sorcin overexpression in HCT116 cells resulted in a significant increase in cell migration and invasion. Sorcin stimulated epithelial-mesenchymal transition through activating PI3K/Akt signaling. (PMID:25567655)
• Drug resistance can be effectively reversed in cisplatin-resistance and adriamycin-resistant myeloma cells through delivery of siRNAs targeting sorcin. (PMID:26045737)
• The authors verified that NS5A of hepatitis C virus interacted with sorcin through domain I of NS5A, and phosphorylation of the threonine residue 155 of sorcin played a crucial role in protein interaction. (PMID:26719254)
• Sorcin is able to limit the toxic effects of the chemotherapeutic agent in the cell. In addition, Sorcin silencing increases cell death upon treatment with doxorubicin, increases the accumulation of doxorubicin in cell nucleus, decreases the expression of MDR1 and doxorubicin efflux via MDR1. (PMID:28726784)
• REVIEW: the relationship of Sorcin with tumors as well as its regulatory mechanisms; Sorcin is increasingly considered as a potential molecular target for therapeutic intervention (PMID:30144438)
• Profiling calcium-dependent interactions between Sorcin and intrinsically disordered regions of human proteome. (PMID:32305337)
• Sorcin is an early marker of neurodegeneration, Ca(2+) dysregulation and endoplasmic reticulum stress associated to neurodegenerative diseases. (PMID:33060591)
• The Ca(2+) -binding protein sorcin stimulates transcriptional activity of the unfolded protein response mediator ATF6. (PMID:33960419)
• A novel homeostatic loop of sorcin drives paclitaxel-resistance and malignant progression via Smad4/ZEB1/miR-142-5p in human ovarian cancer. (PMID:34163033)
• Sorcin Activates the Brain PMCA and Blocks the Inhibitory Effects of Molecular Markers of Alzheimer’s Disease on the Pump Activity. (PMID:34205207)
• Sorcin promotes proliferation of hepatocellular carcinoma by regulating VEGFA/B via PI3K pathway. (PMID:38536659)

Cross-species orthologs

12 orthologs

Organism	Symbol	Gene ID
danio_rerio	sri	ENSDARG00000058593
mus_musculus	Sri	ENSMUSG00000003161
rattus_norvegicus	Sri	ENSRNOG00000049780
caenorhabditis_elegans		WBGENE00000542
caenorhabditis_elegans	clp-3	WBGENE00000544
caenorhabditis_elegans		WBGENE00000546
caenorhabditis_elegans		WBGENE00000547
caenorhabditis_elegans		WBGENE00006606
caenorhabditis_elegans	clp-8	WBGENE00009695
caenorhabditis_elegans	clpr-3	WBGENE00010417
caenorhabditis_elegans	clpr-1	WBGENE00012233
caenorhabditis_elegans	clpr-3	WBGENE00013184

Paralogs (20): CAPN1 (ENSG00000014216), CAPN6 (ENSG00000077274), CAPN3 (ENSG00000092529), CAPN15 (ENSG00000103326), GCA (ENSG00000115271), ADGB (ENSG00000118492), CAPNS1 (ENSG00000126247), CAPN7 (ENSG00000131375), CAPN9 (ENSG00000135773), CAPN11 (ENSG00000137225), CAPN10 (ENSG00000142330), CAPN5 (ENSG00000149260), PEF1 (ENSG00000162517), CAPN2 (ENSG00000162909), CAPN13 (ENSG00000162949), CAPN12 (ENSG00000182472), CAPN8 (ENSG00000203697), CAPN14 (ENSG00000214711), PDCD6 (ENSG00000249915), CAPNS2 (ENSG00000256812)

Protein

Protein identifiers

Sorcin — P30626 (reviewed: P30626)

Alternative names: 22 kDa protein, CP-22, V19

All UniProt accessions (4): P30626, B4DHQ6, C9J0K6, E9PG82

UniProt curated annotations — full annotation on UniProt →

Function. Calcium-binding protein that modulates excitation-contraction coupling in the heart. Contributes to calcium homeostasis in the heart sarcoplasmic reticulum. Modulates the activity of RYR2 calcium channels.

Subunit / interactions. Homodimer. Interacts with GCA, RYR2 and ANXA7.

Subcellular location. Cytoplasm. Sarcoplasmic reticulum membrane.

Tissue specificity. Detected in cardiac myocytes.

Miscellaneous. This protein is encoded by an amplified gene in multidrug-resistant cells. This protein has been shown to bind calcium with high affinity.

Isoforms (3)

UniProt ID	Names	Canonical?
P30626-1	1	yes
P30626-2	2
P30626-3	3

RefSeq proteins (4): NP_001243820, NP_001243821, NP_003121, NP_944490 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002048	EF_hand_dom	Domain
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR018247	EF_Hand_1_Ca_BS	Binding_site

Pfam: PF13499, PF13833

UniProt features (37 total): helix 11, binding site 10, strand 7, domain 4, splice variant 2, chain 1, mutagenesis site 1, turn 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
4USL	X-RAY DIFFRACTION	1.65
4UPG	X-RAY DIFFRACTION	2.1
1JUO	X-RAY DIFFRACTION	2.2
4U8D	X-RAY DIFFRACTION	2.3
2JC2	X-RAY DIFFRACTION	2.5
5MRA	X-RAY DIFFRACTION	3.74

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P30626-F1	86.12	0.73

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 (10): 113; 115; 117; 119; 124; 83; 85; 87; 89; 94

Mutagenesis-validated functional residues (1):

Position	Phenotype
112	reduces affinity for calcium 5-fold.

Function

Pathways and Gene Ontology

Reactome pathways

14 pathways

ID	Pathway
R-HSA-2672351	Stimuli-sensing channels
R-HSA-418359	Reduction of cytosolic Ca++ levels
R-HSA-425561	Sodium/Calcium exchangers
R-HSA-5578775	Ion homeostasis
R-HSA-936837	Ion transport by P-type ATPases
R-HSA-109582	Hemostasis
R-HSA-382551	Transport of small molecules
R-HSA-397014	Muscle contraction
R-HSA-418346	Platelet homeostasis
R-HSA-418360	Platelet calcium homeostasis
R-HSA-425393
R-HSA-425407	SLC-mediated transmembrane transport
R-HSA-5576891	Cardiac conduction
R-HSA-983712	Ion channel transport

MSigDB gene sets: 389 (showing top): GOBP_POSITIVE_REGULATION_OF_CALCIUM_ION_TRANSPORT, CHIARADONNA_NEOPLASTIC_TRANSFORMATION_KRAS_DN, GOBP_CIRCULATORY_SYSTEM_PROCESS, KANG_FLUOROURACIL_RESISTANCE_UP, KAAB_FAILED_HEART_ATRIUM_DN, GOCC_SECRETORY_GRANULE, GOBP_NEGATIVE_REGULATION_OF_MUSCLE_CONTRACTION, GOBP_INSULIN_SECRETION, GOBP_CELLULAR_RESPONSE_TO_CARBOHYDRATE_STIMULUS, GOBP_REGULATION_OF_HORMONE_LEVELS, IVANOVA_HEMATOPOIESIS_MATURE_CELL, GOBP_HORMONE_TRANSPORT, GNF2_MCM5, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, ACEVEDO_LIVER_CANCER_WITH_H3K27ME3_UP

GO Biological Process (13): calcium ion transport (GO:0006816), signal transduction (GO:0007165), negative regulation of heart rate (GO:0010459), regulation of cell communication by electrical coupling (GO:0010649), regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum (GO:0010880), positive regulation of release of sequestered calcium ion into cytosol (GO:0051281), regulation of calcium ion transport (GO:0051924), negative regulation of cardiac muscle contraction (GO:0055118), regulation of insulin secretion involved in cellular response to glucose stimulus (GO:0061178), regulation of cardiac muscle cell contraction (GO:0086004), regulation of relaxation of muscle (GO:1901077), regulation of cell communication by electrical coupling involved in cardiac conduction (GO:1901844), regulation of gene expression (GO:0010468)

GO Molecular Function (12): protease binding (GO:0002020), signaling receptor binding (GO:0005102), calcium channel regulator activity (GO:0005246), calcium ion binding (GO:0005509), identical protein binding (GO:0042802), transmembrane transporter binding (GO:0044325), protein heterodimerization activity (GO:0046982), DNA-binding transcription factor binding (GO:0140297), protein sequestering activity (GO:0140311), transcription regulator inhibitor activity (GO:0140416), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (14): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), membrane (GO:0016020), sarcoplasmic reticulum (GO:0016529), Z disc (GO:0030018), T-tubule (GO:0030315), sarcoplasmic reticulum membrane (GO:0033017), extracellular exosome (GO:0070062), plasma membrane (GO:0005886), endomembrane system (GO:0012505), vesicle (GO:0031982), chromaffin granule membrane (GO:0042584)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Ion channel transport	2
Transport of small molecules	2
Platelet calcium homeostasis	1
Metal ion SLC transporters	1
Cardiac conduction	1
Hemostasis	1
Platelet homeostasis	1
Muscle contraction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	7
protein binding	4
negative regulation of heart contraction	2
regulation of release of sequestered calcium ion into cytosol	2
regulation of cardiac muscle contraction	2
metal ion transport	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
regulation of heart rate	1
cell communication by electrical coupling	1
regulation of cell communication	1
release of sequestered calcium ion into cytosol by sarcoplasmic reticulum	1
release of sequestered calcium ion into cytosol	1
positive regulation of calcium ion transmembrane transport	1
calcium ion transport	1
regulation of metal ion transport	1
negative regulation of striated muscle contraction	1
cardiac muscle contraction	1
insulin secretion involved in cellular response to glucose stimulus	1
regulation of insulin secretion	1
regulation of cellular localization	1
cardiac muscle cell contraction	1
regulation of actin filament-based movement	1
relaxation of muscle	1
regulation of muscle system process	1
regulation of cell communication by electrical coupling	1
cell communication by electrical coupling involved in cardiac conduction	1
gene expression	1
regulation of macromolecule biosynthetic process	1
enzyme binding	1
calcium channel activity	1
ion channel regulator activity	1
metal ion binding	1
protein dimerization activity	1
transcription factor binding	1
molecular sequestering activity	1
regulation of gene expression	1

Protein interactions and networks

STRING

878 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SRI	RYR2	Q92736	946
SRI	PSEN2	P49810	917
SRI	TRDN	Q13061	913
SRI	CALM1	P02593	863
SRI	CALML3	P27482	842
SRI	CALML5	Q9NZT1	842
SRI	CALML6	Q8TD86	841
SRI	CALML4	Q96GE6	841
SRI	ANXA7	P20073	830
SRI	NEK8	Q86SG6	727
SRI	NEK9	Q8TD19	693
SRI	ASPH	Q12797	680
SRI	AURKB	Q96GD4	673
SRI	LGALS1	P09382	640
SRI	CYBB	P04839	635

IntAct

55 interactions, top by confidence:

A	B	Type	Score
CALCOCO2	SRI	psi-mi:“MI:0915”(physical association)	0.740
SRI	CALCOCO2	psi-mi:“MI:0915”(physical association)	0.740
ANAPC2	BUB1B	psi-mi:“MI:0914”(association)	0.730
SRI	STAT3	psi-mi:“MI:0915”(physical association)	0.630
TCF12	SRI	psi-mi:“MI:0915”(physical association)	0.560
SRI	PDE4C	psi-mi:“MI:0915”(physical association)	0.560
SRI	PRR13	psi-mi:“MI:0915”(physical association)	0.560
SRI	TCF12	psi-mi:“MI:0915”(physical association)	0.560
PDE4C	SRI	psi-mi:“MI:0915”(physical association)	0.560
SRI	USHBP1	psi-mi:“MI:0915”(physical association)	0.560
SRI	SRI	psi-mi:“MI:0915”(physical association)	0.550
SRI	PSEN2	psi-mi:“MI:0407”(direct interaction)	0.540
PSEN2	SRI	psi-mi:“MI:0915”(physical association)	0.540
VCAM1	PSMD11	psi-mi:“MI:0914”(association)	0.530
SRI	Ryr2	psi-mi:“MI:0407”(direct interaction)	0.440
SRI	SRPK2	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
SRI	GCA	psi-mi:“MI:0915”(physical association)	0.370
EBNA2	SRI	psi-mi:“MI:0915”(physical association)	0.370
SRI	SMAD2	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (101): CALCOCO2 (Two-hybrid), GCA (Two-hybrid), SRI (Two-hybrid), STAT3 (Two-hybrid), SRI (Two-hybrid), TCF12 (Two-hybrid), CALCOCO2 (Two-hybrid), PRR13 (Two-hybrid), CALCOCO2 (Two-hybrid), SRI (Two-hybrid), C12orf57 (Co-fractionation), MPI (Co-fractionation), PDCD6IP (Co-fractionation), PIR (Co-fractionation), SOD1 (Co-fractionation)

ESM2 similar proteins: A0JN27, A5PJI5, G3MWR8, G3V9T7, O43681, O54984, O94925, P04163, P05943, P08207, P22234, P27003, P30626, P33764, P51583, P60902, P60903, P62504, P62818, P62819, Q13888, Q15303, Q2TBV5, Q2YDM2, Q3MHC2, Q5HZM6, Q5NVE6, Q5R4U9, Q5RB59, Q5RIC0, Q5TA45, Q5TDH0, Q5ZHS1, Q5ZIH0, Q61527, Q62956, Q64119, Q6NVL5, Q6P1K8, Q6PH85

Diamond homologs: A6NHC0, A8MX76, G3V7W1, O08529, O08688, O14815, O15484, O23184, O35350, O35646, O35920, O75808, O88456, O88501, P00789, P04574, P04632, P05044, P06813, P06814, P06815, P07384, P13135, P16259, P17655, P20807, P27398, P27730, P28676, P30626, P34308, P35750, P43367, P43368, P51186, P97571, Q07009, Q11002, Q22036, Q27970

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
PLK1	unknown	SRI	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	27
Likely benign	0
Benign	10

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
225049	NM_003130.4(SRI):c.206-1G>A	Pathogenic

SpliceAI

1276 predictions. Top by Δscore:

Variant	Effect	Δscore
7:88206501:TGAA:T	acceptor_gain	1.0000
7:88206505:C:CC	acceptor_gain	1.0000
7:88208505:A:AC	donor_gain	1.0000
7:88208506:C:CC	donor_gain	1.0000
7:88208506:CAT:C	donor_gain	1.0000
7:88208562:CTGT:C	acceptor_gain	1.0000
7:88208564:GTCT:G	acceptor_loss	1.0000
7:88208566:C:CC	acceptor_gain	1.0000
7:88209334:CTCA:C	donor_loss	1.0000
7:88209335:TCACC:T	donor_loss	1.0000
7:88209337:A:AC	donor_gain	1.0000
7:88209337:AC:A	donor_gain	1.0000
7:88209338:C:CA	donor_gain	1.0000
7:88209338:CC:C	donor_gain	1.0000
7:88209338:CCT:C	donor_gain	1.0000
7:88209338:CCTGT:C	donor_gain	1.0000
7:88209448:AAATC:A	acceptor_gain	1.0000
7:88209449:AATC:A	acceptor_gain	1.0000
7:88209451:TC:T	acceptor_gain	1.0000
7:88209452:CC:C	acceptor_gain	1.0000
7:88209453:C:CC	acceptor_gain	1.0000
7:88209453:C:T	acceptor_gain	1.0000
7:88210883:T:TA	donor_gain	1.0000
7:88217191:CCTTT:C	acceptor_gain	1.0000
7:88217195:T:TC	acceptor_gain	1.0000
7:88218853:GCTAA:G	donor_loss	1.0000
7:88218854:CTAA:C	donor_loss	1.0000
7:88218855:TAACC:T	donor_loss	1.0000
7:88218856:AAC:A	donor_loss	1.0000
7:88218857:ACC:A	donor_loss	1.0000

AlphaMissense

1297 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:88208558:A:C	F173L	1.000
7:88208558:A:T	F173L	1.000
7:88208560:A:G	F173L	1.000
7:88210053:A:C	F109L	1.000
7:88210053:A:T	F109L	1.000
7:88210055:A:G	F109L	1.000
7:88210067:A:G	W105R	1.000
7:88210067:A:T	W105R	1.000
7:88210906:G:C	C75W	1.000
7:88210907:C:T	C75Y	1.000
7:88217166:A:G	L54S	1.000
7:88218877:A:C	F39L	1.000
7:88218877:A:T	F39L	1.000
7:88218879:A:G	F39L	1.000
7:88206502:G:C	F191L	0.999
7:88206502:G:T	F191L	0.999
7:88206503:A:G	F191S	0.999
7:88206504:A:G	F191L	0.999
7:88208548:C:G	D177H	0.999
7:88208550:C:G	R176P	0.999
7:88208559:A:G	F173S	0.999
7:88209341:G:A	T170I	0.999
7:88209344:A:G	L169P	0.999
7:88209353:A:G	L166P	0.999
7:88209359:A:T	V164D	0.999
7:88209364:G:C	C162W	0.999
7:88209366:A:G	C162R	0.999
7:88209381:C:G	D157H	0.999
7:88209994:A:G	L129P	0.999
7:88210042:T:A	D113V	0.999

dbSNP variants (sampled 300 via entrez): RS1000317431 (7:88221600 A>C), RS1000369871 (7:88221128 T>G), RS1000410837 (7:88224814 C>A,T), RS1000477239 (7:88227323 A>T), RS1000529454 (7:88220345 A>C), RS1000942631 (7:88219851 C>A,T), RS1000955586 (7:88219365 G>A,C,T), RS1001139492 (7:88212018 C>T), RS1001225348 (7:88226465 A>G), RS1001468086 (7:88211526 T>C,G), RS1001734382 (7:88218513 C>T), RS1001744118 (7:88218188 G>T), RS1001928050 (7:88220700 G>A,T), RS1001944945 (7:88227388 C>T), RS1001980422 (7:88220389 T>C)

Disease associations

OMIM: gene MIM:182520 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
hypertrophic cardiomyopathy	Refuted Evidence	Autosomal dominant

Mondo (1): hypertrophic cardiomyopathy (MONDO:0005045)

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D002312	Cardiomyopathy, Hypertrophic	C14.280.238.100; C14.280.484.048.750.070.160

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066922 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects binding, increases reaction, decreases expression, affects cotreatment, increases abundance (+1 more)	4
Valproic Acid	affects expression, increases expression	4
bisphenol A	decreases methylation, increases expression	2
tamibarotene	affects expression, increases expression	2
Arsenic	affects methylation, affects cotreatment, increases abundance, increases expression	2
Doxorubicin	decreases expression, decreases response to substance	2
Tretinoin	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
bisphenol F	increases expression	1
methylmercuric chloride	decreases expression	1
alpha phellandrene	increases expression	1
triphenyl phosphate	affects expression	1
glycidyl methacrylate	decreases expression	1
pyrogallol 1,3-dimethyl ether	decreases expression, affects cotreatment	1
tetrahydropalmatine	decreases expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, increases reaction	1
methylparaben	decreases expression	1
cobaltous chloride	decreases expression	1
manganese chloride	increases abundance, increases expression, affects cotreatment	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
4-aminophenylarsenoxide	affects binding, decreases reaction	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
chromium hexavalent ion	affects expression	1
CGP 52608	affects binding, increases reaction	1
calfactant	affects cotreatment, decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
ICG 001	increases expression	1
bisphenol B	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
CHEMBL5652523	Binding	Binding affinity to human SRI 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

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_KU06	HeLa SilenciX SORCIN	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00879060	PHASE4	COMPLETED	Clinical and Therapeutic Implications of Fibrosis in Hypertrophic Cardiomyopathy
NCT01721967	PHASE4	COMPLETED	Ranolazine for the Treatment of Chest Pain in HCM Patients
NCT02948998	PHASE4	UNKNOWN	Evaluating the Effect of Spironolactone on Hypertrophic Cardiomyopathy
NCT03249272	PHASE4	TERMINATED	Microvascular Dysfunction in Nonischemic Cardiomyopathy: Insights From CMR Assessment of Coronary Flow Reserve
NCT04133532	PHASE4	COMPLETED	Effect of Metoprolol in Post Alcohol Septal Ablation Patients With Hypertrophic Cardiomyopathy
NCT06401343	PHASE4	RECRUITING	Use of SGLT2i in noHCM With HFpEF
NCT07103655	PHASE4	NOT_YET_RECRUITING	The Therapeutic Value of Mavacamten in Hypertrophic Cardiomyopathy With Mid-to-Apical Left Ventricular Obstruction
NCT07600177	PHASE4	RECRUITING	Mavacamten to Aficamten Transition in Patients With Obstructive Hypertrophic Cardiomyopathy
NCT00317967	PHASE3	COMPLETED	Study to Determine if Atorvastatin Reduces Size and Stiffness of Muscle in the Left Ventricle of the Heart
NCT00698074	PHASE3	UNKNOWN	Diastolic Ventricular Interaction and the Effects of Biventricular Pacing in Hypertrophic Cardiomyopathy
NCT00821353	PHASE3	COMPLETED	Antiarrhythmic Therapy Versus Catheter Ablation for Atrial Fibrillation in Hypertrophic Cardiomyopathy
NCT02431221	PHASE3	WITHDRAWN	Efficacy, Safety, and Tolerability of Perhexiline in Subjects With Hypertrophic Cardiomyopathy and Heart Failure
NCT03470545	PHASE3	COMPLETED	Clinical Study to Evaluate Mavacamten (MYK-461) in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy
NCT05174416	PHASE3	COMPLETED	A Study to Evaluate the Efficacy and Safety of Mavacamten in Chinese Adults With Symptomatic Obstructive HCM
NCT05182658	PHASE3	ACTIVE_NOT_RECRUITING	Empagliflozin in Hypertrophic Cardiomyopathy
NCT05186818	PHASE3	COMPLETED	Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM
NCT05767346	PHASE3	COMPLETED	Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Metoprolol Succinate in Adults With Symptomatic oHCM
NCT06116968	PHASE3	COMPLETED	An Open-Label Study of Aficamten for Chinese Patients With Symptomatic oHCM
NCT06873828	PHASE3	NOT_YET_RECRUITING	Evaluation of the Efficacy and Safety of Wearable ECG (AT-Patch) in Patients With Hypertrophic Cardiomyopathy Requiring 48-Hour Holter MonitoringEvaluation of the Efficacy and Safety of Wearable ECG (AT-Patch) in Patients With Hypertrophic Cardiomyopathy Requiring 48-Hour Holter Monitoring
NCT07021976	PHASE3	RECRUITING	A Phase III Trial of HRS-1893 in Patients With Obstructive Hypertrophic Cardiomyopathy
NCT07023341	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Learn More About How Well Aficamten Works in Japanese Participants With Symptomatic Obstructive Hypertrophic Cardiomyopathy
NCT07202897	PHASE3	NOT_YET_RECRUITING	LA-HCM Study : Rivaroxaban for Antithrombotic Prevention in Hypertrophic Cardiomyopathy Patients With Abnormal Left Atrial Strain.
NCT00001631	PHASE2	COMPLETED	Study of Blood Flow in Heart Muscle
NCT00001894	PHASE2	COMPLETED	A Comparison of Two Treatments: Pacemaker and Percutaneous Transluminal Septal Ablation for Hypertrophic Cardiomyopathy
NCT00001960	PHASE2	COMPLETED	Studying the Effectiveness of Pacemaker Therapy in Children Who Have Thickened Heart Muscle
NCT00011076	PHASE2	COMPLETED	Pirfenidone to Treat Hypertrophic Cardiomyopathy
NCT00035386	PHASE2	COMPLETED	Alcohol Septal Ablation in Obstructive Hypertrophic Cardiomyopathy: A Pilot Study
NCT00430833	PHASE2	UNKNOWN	CHANCE - Candesartan in Hypertrophic Cardiomyopathy
NCT00500552	PHASE2	COMPLETED	Perhexiline Therapy in Patients With Hypertrophic Cardiomyopathy
NCT01150461	PHASE2	COMPLETED	Effect of Losartan in Patients With Nonobstructive Hypertrophic Cardiomyopathy
NCT01230918	PHASE2	TERMINATED	Study to Develop a Non-invasive Marker for Monitoring Myocardial Fibrosis
NCT01447654	PHASE2	COMPLETED	Inhibition of the Renin Angiotensin System With Losartan in Patients With Hypertrophic Cardiomyopathy
NCT01696370	PHASE2	UNKNOWN	Trimetazidine Therapy in Hypertrophic Cardiomyopathy
NCT01912534	PHASE2	COMPLETED	Valsartan for Attenuating Disease Evolution In Early Sarcomeric HCM
NCT02590809	PHASE2	COMPLETED	Hypertrophic Cardiomyopathy Symptom Release by BX1514M
NCT03496168	PHASE2	COMPLETED	Extension Study of Mavacamten (MYK-461) in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy Previously Enrolled in PIONEER
NCT03532802	PHASE2	COMPLETED	The Effect of Metoprolol in Patients With Hypertrophic Obstructive Cardiomyopathy.
NCT03832660	PHASE2	COMPLETED	Sacubitril/Valsartan vs Lifestyle in Hypertrophic Cardiomyopathy
NCT04219826	PHASE2	COMPLETED	Dose-finding Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of CK-3773274 in Adults With Hypertrophic Cardiomyopathy
NCT04426578	PHASE2	UNKNOWN	Role of Perhexiline in Hypertrophic Cardiomyopathy