STAC2

Summary

STAC2 (SH3 and cysteine rich domain 2, HGNC:23990) is a protein-coding gene on chromosome 17q12, encoding SH3 and cysteine-rich domain-containing protein 2 (Q6ZMT1). Plays a redundant role in promoting the expression of calcium channel CACNA1S at the cell membrane, and thereby contributes to increased channel activity.

This gene encodes a protein containing an SH3 domain and a zinc finger domain. The encoded protein has been shown to regulate calcium channel inactivation in a human cell line. Reduced expression of this gene has been observed in human heart failure.

Source: NCBI Gene 342667 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 79 total — 1 likely-pathogenic
• MANE Select transcript: NM_198993

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23990
Approved symbol	STAC2
Name	SH3 and cysteine rich domain 2
Location	17q12
Locus type	gene with protein product
Status	Approved
Aliases	24b2
Ensembl gene	ENSG00000141750
Ensembl biotype	protein_coding
OMIM	621356
Entrez	342667

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 5 protein_coding, 1 nonsense_mediated_decay

ENST00000333461, ENST00000584501, ENST00000879293, ENST00000925549, ENST00000945425, ENST00000945426

RefSeq mRNA: 2 — MANE Select: NM_198993 NM_001351360, NM_198993

CCDS: CCDS11335

Canonical transcript exons

ENST00000333461 — 11 exons

Exon	Start	End
ENSE00001201811	39225413	39225945
ENSE00001201821	39210541	39212396
ENSE00001328665	39217867	39218173
ENSE00003498924	39213507	39213558
ENSE00003506365	39212995	39213132
ENSE00003516329	39214791	39214861
ENSE00003545503	39216810	39216900
ENSE00003552789	39214951	39215023
ENSE00003572365	39217076	39217173
ENSE00003659870	39215118	39215230
ENSE00003668174	39214233	39214330

Expression profiles

Bgee: expression breadth ubiquitous, 164 present calls, max score 92.79.

FANTOM5 (CAGE): breadth broad, TPM avg 2.6667 / max 615.3100, expressed in 322 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
165591	1.1724	177
165595	0.8496	146
165594	0.2588	63
165592	0.1718	48
165593	0.1472	59
165590	0.0669	30

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
popliteal artery	UBERON:0002250	92.79	gold quality
tibial artery	UBERON:0007610	92.75	gold quality
right frontal lobe	UBERON:0002810	92.03	gold quality
anterior cingulate cortex	UBERON:0009835	90.44	gold quality
skin of leg	UBERON:0001511	89.73	gold quality
Brodmann (1909) area 9	UBERON:0013540	89.57	gold quality
aorta	UBERON:0000947	89.31	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	88.56	gold quality
descending thoracic aorta	UBERON:0002345	88.15	gold quality
prefrontal cortex	UBERON:0000451	87.52	gold quality
pancreatic ductal cell	CL:0002079	87.04	silver quality
frontal cortex	UBERON:0001870	86.86	gold quality
neocortex	UBERON:0001950	86.80	gold quality
primary visual cortex	UBERON:0002436	86.20	gold quality
zone of skin	UBERON:0000014	85.42	gold quality
right hemisphere of cerebellum	UBERON:0014890	85.42	gold quality
thoracic aorta	UBERON:0001515	84.91	gold quality
cerebellar hemisphere	UBERON:0002245	84.69	gold quality
ascending aorta	UBERON:0001496	84.66	gold quality
cerebellar cortex	UBERON:0002129	84.61	gold quality
occipital lobe	UBERON:0002021	84.23	gold quality
skin of abdomen	UBERON:0001416	84.21	gold quality
cerebral cortex	UBERON:0000956	84.18	gold quality
nasal cavity epithelium	UBERON:0005384	83.83	gold quality
cerebellar vermis	UBERON:0004720	83.65	gold quality
cerebellum	UBERON:0002037	83.57	gold quality
putamen	UBERON:0001874	81.81	gold quality
nucleus accumbens	UBERON:0001882	81.75	gold quality
tibialis anterior	UBERON:0001385	81.33	silver quality
sperm	CL:0000019	80.81	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	19.53
E-CURD-135	no	787.20

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

107 targeting STAC2, 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-4673	100.00	66.64	1490
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-23B-5P	99.98	66.07	587
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-23A-5P	99.94	65.39	468
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-4728-5P	99.85	69.39	4718
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-6785-5P	99.82	68.68	4428
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-26A-5P	99.78	73.52	2303
HSA-MIR-26B-5P	99.78	73.51	2305
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-4306	99.72	70.50	3630

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Stac2	ENSMUSG00000017400
rattus_norvegicus	Stac2	ENSRNOG00000004805

Paralogs (2): STAC (ENSG00000144681), STAC3 (ENSG00000185482)

Protein

Protein identifiers

SH3 and cysteine-rich domain-containing protein 2 — Q6ZMT1 (reviewed: Q6ZMT1)

Alternative names: 24b2/STAC2, Src homology 3 and cysteine-rich domain-containing protein 2

All UniProt accessions (3): D0IN09, Q6ZMT1, J3QKZ0

UniProt curated annotations — full annotation on UniProt →

Function. Plays a redundant role in promoting the expression of calcium channel CACNA1S at the cell membrane, and thereby contributes to increased channel activity. Slows down the inactivation rate of the calcium channel CACNA1C.

Subunit / interactions. Interacts (via SH3 domains) with CACNA1S. Interacts (via SH3 domains) with CACNA1C. Has much lower affinity for CACNA1C than for CACNA1S.

Subcellular location. Cytoplasm. Cytosol. Cell membrane. Sarcolemma.

Isoforms (2)

UniProt ID	Names	Canonical?
Q6ZMT1-1	1	yes
Q6ZMT1-2	2

RefSeq proteins (2): NP_001338289, NP_945344* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001452	SH3_domain	Domain
IPR002219	PKC_DAG/PE	Domain
IPR035509	Stac2_SH3	Domain
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR039688	STAC1/2/3	Family
IPR046349	C1-like_sf	Homologous_superfamily

Pfam: PF00130, PF07653, PF14604, PF16664

UniProt features (30 total): strand 10, helix 4, region of interest 4, compositionally biased region 3, mutagenesis site 3, domain 2, chain 1, modified residue 1, splice variant 1, zinc finger region 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
6B26	X-RAY DIFFRACTION	1.2
6B27	X-RAY DIFFRACTION	1.73
6B28	X-RAY DIFFRACTION	2.55

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6ZMT1-F1	67.09	0.29

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 (1): 48

Mutagenesis-validated functional residues (3):

Position	Phenotype
306	mildly decreased affinity for cacna1s.
329	loss of interaction with cacna1s.
347	no effect on the structure of the two sh3 domains.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 145 (showing top): GOBP_POSITIVE_REGULATION_OF_CATION_CHANNEL_ACTIVITY, RORA1_01, GOBP_POSITIVE_REGULATION_OF_TRANSPORTER_ACTIVITY, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_REGULATION_OF_VOLTAGE_GATED_CALCIUM_CHANNEL_ACTIVITY, TGACCTY_ERR1_Q2, GOBP_MULTICELLULAR_ORGANISMAL_MOVEMENT, LHX3_01, GOBP_SKELETAL_MUSCLE_CONTRACTION, GOBP_PROTEIN_LOCALIZATION_TO_CELL_PERIPHERY, GOBP_POSITIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION_TO_CELL_PERIPHERY, GOBP_POSITIVE_REGULATION_OF_MOLECULAR_FUNCTION

GO Biological Process (3): skeletal muscle contraction (GO:0003009), positive regulation of voltage-gated calcium channel activity (GO:1901387), positive regulation of protein localization to plasma membrane (GO:1903078)

GO Molecular Function (3): zinc ion binding (GO:0008270), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (6): cytosol (GO:0005829), cytoplasmic side of plasma membrane (GO:0009898), sarcolemma (GO:0042383), cytoplasm (GO:0005737), plasma membrane (GO:0005886), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
plasma membrane	2
striated muscle contraction	1
musculoskeletal movement	1
voltage-gated calcium channel activity	1
regulation of voltage-gated calcium channel activity	1
positive regulation of cation channel activity	1
protein localization to plasma membrane	1
regulation of protein localization to plasma membrane	1
positive regulation of protein localization to cell periphery	1
positive regulation of protein localization to membrane	1
transition metal ion binding	1
binding	1
cation binding	1
cytoplasm	1
cytoplasmic side of membrane	1
intracellular anatomical structure	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

1759 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
STAC2	CACNA1S	Q13698	622
STAC2	CACNA1C	Q13936	603
STAC2	STK32A	Q8WU08	472
STAC2	RABGGTA	Q92696	462
STAC2	TSC22D2	O75157	458
STAC2	PKDCC	Q504Y2	430
STAC2	DOCK5	Q9H7D0	418
STAC2	UBASH3B	Q8TF42	411
STAC2	ING2	Q9H160	406
STAC2	LCN10	Q6JVE6	406
STAC2	VARS1	P26640	404
STAC2	SPINT2	O43291	400
STAC2	ESR1	P03372	390
STAC2	LCN6	P62502	379
STAC2	ABL1	P00519	377

IntAct

15 interactions, top by confidence:

A	B	Type	Score
ATXN1	STAC2	psi-mi:“MI:0915”(physical association)	0.670
STAC2	LNX1	psi-mi:“MI:0915”(physical association)	0.560
LNX1	STAC2	psi-mi:“MI:0915”(physical association)	0.560
PRKAA2	STAC2	psi-mi:“MI:0915”(physical association)	0.560
ECE1	STAC2	psi-mi:“MI:0915”(physical association)	0.370
STAC2	EIF1AX	psi-mi:“MI:0914”(association)	0.350
STAC2	SNX1	psi-mi:“MI:0914”(association)	0.350
PRKAA2	STAC2	psi-mi:“MI:0915”(physical association)	0.000
ATXN1	STAC2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (37): STAC2 (Two-hybrid), BRCA1 (Two-hybrid), STAC2 (Two-hybrid), PRKAA2 (Two-hybrid), URM1 (Affinity Capture-MS), METAP2 (Affinity Capture-MS), SNX1 (Affinity Capture-MS), SNX6 (Affinity Capture-MS), EIF1AX (Affinity Capture-MS), ADO (Affinity Capture-MS), STAC (Affinity Capture-MS), SNX5 (Affinity Capture-MS), ANKLE2 (Affinity Capture-MS), RBM12 (Affinity Capture-MS), F11R (Affinity Capture-MS)

ESM2 similar proteins: A0JN71, A4IFK0, A5PMU4, A6QQV9, O15034, O15040, O62666, O62674, O62675, O62676, O62677, O62678, O75995, P49796, P52734, P59672, P78314, P97432, P98174, Q06649, Q0V8R5, Q13905, Q14596, Q3U0J8, Q501R9, Q53GL0, Q5BJM5, Q5F3C8, Q5RC94, Q5SUE8, Q6AI12, Q6ZMT1, Q7Z5H3, Q80U40, Q80UZ0, Q80XA6, Q80YS6, Q8BL80, Q8K352, Q8N556

Diamond homologs: A0JNJ1, A1CEK6, A1DFN5, A2QW93, A4RF61, A6QLK6, A7A261, F1LRS8, O35179, O35964, O43307, O74749, O75791, O75886, O88811, O89100, O93436, P02549, P07751, P09215, P09216, P10830, P13395, P16054, P16086, P16546, P23298, P24723, P28867, P29355, P32793, P34885, P38753, P43603, P53281, P62993, P62994, P70297, P87379, P97306

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	74
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
208390	NM_198993.5(STAC2):c.257G>A (p.Arg86Lys)	Likely pathogenic

SpliceAI

1737 predictions. Top by Δscore:

Variant	Effect	Δscore
17:39212394:GATC:G	acceptor_loss	1.0000
17:39212403:C:CT	acceptor_gain	1.0000
17:39212403:C:T	acceptor_gain	1.0000
17:39212404:A:T	acceptor_gain	1.0000
17:39212991:TCACC:T	donor_loss	1.0000
17:39212992:CA:C	donor_loss	1.0000
17:39212993:A:AC	donor_gain	1.0000
17:39212993:AC:A	donor_gain	1.0000
17:39212994:C:CT	donor_gain	1.0000
17:39212994:C:G	donor_loss	1.0000
17:39212994:CC:C	donor_gain	1.0000
17:39212994:CCT:C	donor_gain	1.0000
17:39212994:CCTG:C	donor_gain	1.0000
17:39213508:TTCC:T	donor_gain	1.0000
17:39214231:A:AC	donor_gain	1.0000
17:39214232:C:CT	donor_gain	1.0000
17:39214232:CTG:C	donor_gain	1.0000
17:39214326:GGGAG:G	acceptor_gain	1.0000
17:39214330:GC:G	acceptor_loss	1.0000
17:39214331:C:CC	acceptor_gain	1.0000
17:39214332:T:C	acceptor_loss	1.0000
17:39214786:CTCA:C	donor_loss	1.0000
17:39214787:TCACC:T	donor_loss	1.0000
17:39214789:A:AC	donor_gain	1.0000
17:39214790:C:CC	donor_gain	1.0000
17:39214790:CCTG:C	donor_gain	1.0000
17:39214858:GATG:G	acceptor_gain	1.0000
17:39214859:ATG:A	acceptor_gain	1.0000
17:39214860:TG:T	acceptor_gain	1.0000
17:39214862:C:CC	acceptor_gain	1.0000

AlphaMissense

2691 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:39214265:A:C	F303L	1.000
17:39214265:A:T	F303L	1.000
17:39214267:A:G	F303L	1.000
17:39212347:A:T	V394D	0.999
17:39213091:A:C	F345L	0.999
17:39213091:A:T	F345L	0.999
17:39213093:A:G	F345L	0.999
17:39213132:C:G	G332R	0.999
17:39213513:C:A	W329C	0.999
17:39213513:C:G	W329C	0.999
17:39213515:A:G	W329R	0.999
17:39213515:A:T	W329R	0.999
17:39214242:A:G	L311P	0.999
17:39214266:A:G	F303S	0.999
17:39214281:A:T	V298D	0.999
17:39217150:A:G	C141R	0.999
17:39213101:G:T	P342Q	0.998
17:39213104:A:G	F341S	0.998
17:39213110:C:T	G339D	0.998
17:39213111:C:G	G339R	0.998
17:39213131:C:T	G332D	0.998
17:39213512:A:G	W330R	0.998
17:39213512:A:T	W330R	0.998
17:39214236:A:G	L313P	0.998
17:39214266:A:C	F303C	0.998
17:39214278:G:T	A299E	0.998
17:39212305:A:G	L408P	0.997
17:39212320:A:T	V403E	0.997
17:39212393:A:G	C379R	0.997
17:39213062:A:T	V355D	0.997

dbSNP variants (sampled 300 via entrez): RS1000270844 (17:39224312 AT>A), RS1000354566 (17:39220667 T>G), RS1000393827 (17:39210117 G>T), RS1000580349 (17:39224104 C>T), RS1000676682 (17:39227088 G>T), RS1000707743 (17:39226662 A>G), RS1000981171 (17:39211269 G>A), RS1001098068 (17:39220260 C>A), RS1001180902 (17:39216320 A>G), RS1001269600 (17:39214736 A>C), RS1001333224 (17:39219800 G>T), RS1001651264 (17:39222036 G>A), RS1001701284 (17:39221751 C>A), RS1001743931 (17:39227852 A>G), RS1001767318 (17:39211100 T>C)

Disease associations

OMIM: gene MIM:621356 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): childhood-onset schizophrenia (MONDO:0957430)

Orphanet (1): Childhood-onset schizophrenia (Orphanet:641496)

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST000624_15	Ulcerative colitis	3.000000e-08
GCST008916_10	Asthma	5.000000e-09
GCST008916_86	Asthma	2.000000e-14
GCST010002_123	Refractive error	1.000000e-24

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Aflatoxin B1	decreases expression	2
propionaldehyde	increases expression	1
lead acetate	decreases expression	1
ethyl-p-hydroxybenzoate	decreases expression	1
terbufos	increases methylation	1
sulforaphane	decreases expression	1
butyraldehyde	increases expression	1
cupric chloride	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression	1
pentanal	increases expression	1
perfluorooctane sulfonic acid	decreases expression	1
clothianidin	increases expression	1
quinocetone	increases expression	1
theaflavin-3,3’-digallate	affects expression	1
Acetaminophen	decreases expression	1
Air Pollutants	increases abundance, decreases expression	1
Aldehydes	increases expression	1
Benzo(a)pyrene	affects methylation	1
Cadmium	increases expression	1
Fonofos	increases methylation	1
Lipopolysaccharides	affects cotreatment, decreases expression	1
Nickel	decreases expression	1
Niclosamide	increases expression	1
Parathion	increases methylation	1
Phenobarbital	decreases expression	1
Rotenone	increases expression	1
Silicon Dioxide	decreases expression	1
Smoke	decreases expression	1
Thiram	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1

Clinical trials (associated diseases)

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