SHANK2

Summary

SHANK2 (SH3 and multiple ankyrin repeat domains 2, HGNC:14295) is a protein-coding gene on chromosome 11q13.3-q13.4, encoding SH3 and multiple ankyrin repeat domains protein 2 (Q9UPX8). Seems to be an adapter protein in the postsynaptic density (PSD) of excitatory synapses that interconnects receptors of the postsynaptic membrane including NMDA-type and metabotropic glutamate receptors, and the actin-based cytoskeleton. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a protein that is a member of the Shank family of synaptic proteins that may function as molecular scaffolds in the postsynaptic density of excitatory synapses. Shank proteins contain multiple domains for protein-protein interaction, including ankyrin repeats, and an SH3 domain. This particular family member contains a PDZ domain, a consensus sequence for cortactin SH3 domain-binding peptides and a sterile alpha motif. The alternative splicing demonstrated in Shank genes has been suggested as a mechanism for regulating the molecular structure of Shank and the spectrum of Shank-interacting proteins in the postsynaptic densities of the adult and developing brain. Alterations in the encoded protein may be associated with susceptibility to autism spectrum disorder. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 22941 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 11
• Clinical variants (ClinVar): 514 total — 21 pathogenic, 27 likely-pathogenic
• Phenotypes (HPO): 2
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_012309

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14295
Approved symbol	SHANK2
Name	SH3 and multiple ankyrin repeat domains 2
Location	11q13.3-q13.4
Locus type	gene with protein product
Status	Approved
Aliases	CTTNBP1, ProSAP1, SHANK, SPANK-3
Ensembl gene	ENSG00000162105
Ensembl biotype	protein_coding
OMIM	603290
Entrez	22941

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 13 protein_coding, 8 protein_coding_CDS_not_defined, 5 retained_intron

ENST00000338508, ENST00000409161, ENST00000409530, ENST00000412252, ENST00000425049, ENST00000426687, ENST00000449116, ENST00000458632, ENST00000460048, ENST00000468619, ENST00000470759, ENST00000482659, ENST00000498519, ENST00000601538, ENST00000606715, ENST00000618363, ENST00000645599, ENST00000654939, ENST00000656230, ENST00000659264, ENST00000686462, ENST00000690983, ENST00000916035, ENST00000916036, ENST00000916037, ENST00000916038

RefSeq mRNA: 3 — MANE Select: NM_012309 NM_001379226, NM_012309, NM_133266

CCDS: CCDS91527

Canonical transcript exons

ENST00000601538 — 26 exons

Exon	Start	End
ENSE00001579341	70500570	70500590
ENSE00001804840	71252425	71252577
ENSE00002478436	70501923	70501931
ENSE00003137337	70502206	70502286
ENSE00003462956	71118829	71119032
ENSE00003476479	71147120	71147338
ENSE00003479555	71056481	71056558
ENSE00003482048	71075159	71075275
ENSE00003547165	71109941	71110049
ENSE00003560968	70896501	70896567
ENSE00003654077	71094537	71094688
ENSE00003655806	71113293	71113364
ENSE00003715775	71092422	71092589
ENSE00003718636	71224697	71224796
ENSE00003725705	70659828	70659952
ENSE00003726350	70698688	70698763
ENSE00003726751	70661596	70661678
ENSE00003731165	70820364	70820682
ENSE00003739206	70502796	70502931
ENSE00003748257	70798443	70798556
ENSE00003748360	70807002	70807171
ENSE00003754926	70490276	70490387
ENSE00003757138	70489328	70489348
ENSE00003757295	70485314	70487720
ENSE00003759217	70492335	70492465
ENSE00003910770	70467854	70473439

Expression profiles

Bgee: expression breadth ubiquitous, 240 present calls, max score 95.35.

FANTOM5 (CAGE): breadth broad, TPM avg 5.2736 / max 143.5361, expressed in 784 samples.

FANTOM5 promoters (20 alternative TSS)

Promoter ID	TPM avg	Samples expressed
121108	2.0860	461
121109	0.9448	366
121089	0.5830	137
121092	0.3232	99
121110	0.2666	163
121094	0.2329	89
121099	0.1185	29
121101	0.1168	50
121096	0.1004	24
121093	0.0707	43

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
Brodmann (1909) area 23	UBERON:0013554	95.35	gold quality
bronchial epithelial cell	CL:0002328	93.65	gold quality
middle temporal gyrus	UBERON:0002771	93.12	gold quality
CA1 field of hippocampus	UBERON:0003881	91.09	gold quality
entorhinal cortex	UBERON:0002728	90.98	gold quality
corpus epididymis	UBERON:0004359	90.45	gold quality
choroid plexus epithelium	UBERON:0003911	90.25	gold quality
endothelial cell	CL:0000115	89.89	gold quality
pigmented layer of retina	UBERON:0001782	89.79	gold quality
primary visual cortex	UBERON:0002436	89.46	gold quality
epithelium of bronchus	UBERON:0002031	89.44	gold quality
orbitofrontal cortex	UBERON:0004167	89.25	gold quality
caput epididymis	UBERON:0004358	89.04	gold quality
Brodmann (1909) area 46	UBERON:0006483	88.83	gold quality
bronchus	UBERON:0002185	88.66	gold quality
cortical plate	UBERON:0005343	88.55	gold quality
superior frontal gyrus	UBERON:0002661	88.19	gold quality
occipital lobe	UBERON:0002021	87.48	gold quality
mucosa of paranasal sinus	UBERON:0005030	86.54	gold quality
buccal mucosa cell	CL:0002336	86.51	gold quality
parotid gland	UBERON:0001831	86.28	gold quality
epithelium of mammary gland	UBERON:0003244	85.87	gold quality
postcentral gyrus	UBERON:0002581	85.69	gold quality
parietal lobe	UBERON:0001872	85.62	gold quality
mammary duct	UBERON:0001765	85.20	gold quality
frontal pole	UBERON:0002795	85.01	gold quality
prefrontal cortex	UBERON:0000451	84.91	gold quality
right uterine tube	UBERON:0001302	84.86	gold quality
epithelial cell of pancreas	CL:0000083	84.63	gold quality
temporal lobe	UBERON:0001871	84.59	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.59

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

297 targeting SHANK2, 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-6867-5P	100.00	82.21	3464
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-9-5P	100.00	72.28	2361
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-3617-3P	99.98	67.86	918
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-4723-5P	99.97	68.70	2034

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 27)

• Shank2 increased the membrane expression and basal activity of NHE3 and attenuated the cAMP-dependent inhibition of NHE3 activity. (PMID:16293618)
• betaPix up-regulates NHE3 membrane expression and activity by Shank2-mediated protein-protein interaction and by activating Rho GTPases in the apical regions of epithelial cells (PMID:20080968)
• we identified de novo copy number variations in the SHANK2 synaptic scaffolding gene in two unrelated individuals with autism-spectrum disorder (ASD) and mental retardation (PMID:20473310)
• dominant negative effect translates into dose-dependent altered cognitive behavior of SHANK2-R462X-expressing mice, with an impact on the penetrance of ASD (PMID:21994763)
• we confirmed that de novo SHANK2 deletions are present in patients with ASD and showed that several SHANK2 variants reduce the number of synapses in vitro (PMID:22346768)
• deletion of ProSAP1/Shank2 results in an early, brain-region-specific upregulation of ionotropic glutamate receptors at the synapse and increased levels of ProSAP2/Shank3 (PMID:22699619)
• Lack of association between NLGN3, NLGN4, SHANK2 and SHANK3 gene variants and autism spectrum disorder in a Chinese population. (PMID:23468870)
• syndapin I functions reflected direct, SH3 domain-mediated associations and functional interactions with ProSAP1/Shank2. (PMID:24751538)
• Knockdown of endogenous Shank2E or overexpression of a dominant-negative Shank2E mutant inhibited the glucocorticoid-mediated increase in CFTR. (PMID:24811177)
• variants in the SHANK2 gene in a schizophrenia patient cohort (PMID:25560758)
• In one family, seven siblings with schizophrenia spectrum disorders each carry a novel private missense variant within the SHANK2 gene. (PMID:27001614)
• The present study demonstrated that depletion of SHANK2 inhibited the osteo/dentinogenic differentiation potentials in human stem cells from apical papilla (PMID:27641545)
• We report a deletion including the SHANK2 gene in a female child with dysmorphic features, microcephaly, and global developmental delay, providing additional evidence for SHANK2 involvement in intellectual disability (PMID:28211979)
• Study provides evidence that a direct regulatory link exists between miR-137 and SHANK2 and supports the finding that miR-137 signaling might be altered in schizophrenia. (PMID:29665782)
• Our results indicate SHANK2 is a susceptibility gene for Autism spectrum disorder (ASD) in Chinese children (PMID:29934968)
• Findings provide evidence for hyperconnectivity and altered transcriptome in SHANK2 neurons derived from autism spectrum disorder subjects. (PMID:30911184)
• Dynamic Change of Shanks Gene mRNA Expression and DNA Methylation in Epileptic Rat Model and Human Patients. (PMID:32564287)
• meQTL and ncRNA functional analyses of 102 GWAS-SNPs associated with depression implicate HACE1 and SHANK2 genes. (PMID:32616021)
• Somatic structural variation targets neurodevelopmental genes and identifies SHANK2 as a tumor suppressor in neuroblastoma. (PMID:32796005)
• Identification of SHANK2 Pathogenic Variants in a Chinese Uygur Population with Schizophrenia. (PMID:32897530)
• Phenotypic spectrum of SHANK2-related neurodevelopmental disorder. (PMID:32987185)
• SHANK2 mutations impair apoptosis, proliferation and neurite outgrowth during early neuronal differentiation in SH-SY5Y cells. (PMID:33483523)
• Genetic Analysis Implicates Dysregulation of SHANK2 in Renal Cell Carcinoma Progression. (PMID:36231770)
• Structural deficits in key domains of Shank2 lead to alterations in postsynaptic nanoclusters and to a neurodevelopmental disorder in humans. (PMID:36450866)
• Remote ischemic conditioning alleviates chronic cerebral hypoperfusion-induced cognitive decline and synaptic dysfunction via the miR-218a-5p/SHANK2 pathway. (PMID:37574039)
• Expression profiles of the autism-related SHANK proteins in the human brain. (PMID:37953224)
• Autism patient-derived SHANK2B[Y29X] mutation affects the development of ALDH1A1 negative dopamine neuron. (PMID:38704506)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	Shank2	ENSMUSG00000037541
rattus_norvegicus	Shank2	ENSRNOG00000050206
drosophila_melanogaster	Prosap	FBGN0040752
caenorhabditis_elegans		WBGENE00006444

Paralogs (2): SHANK1 (ENSG00000161681), SHANK3 (ENSG00000251322)

Protein

Protein identifiers

SH3 and multiple ankyrin repeat domains protein 2 — Q9UPX8 (reviewed: Q9UPX8)

Alternative names: Cortactin-binding protein 1, Proline-rich synapse-associated protein 1

All UniProt accessions (8): A0A2R8Y2H5, A0A590UJ45, A0A590UJF3, A6NHU9, Q9UPX8, E7EUA2, H0Y7S5, H7BZV1

UniProt curated annotations — full annotation on UniProt →

Function. Seems to be an adapter protein in the postsynaptic density (PSD) of excitatory synapses that interconnects receptors of the postsynaptic membrane including NMDA-type and metabotropic glutamate receptors, and the actin-based cytoskeleton. May play a role in the structural and functional organization of the dendritic spine and synaptic junction.

Subunit / interactions. Is part of a complex with DLG4/PSD-95 and DLGAP1/GKAP. Interacts with CTTN/cortactin SH3 domain, DLGAP1/GKAP and alpha-latrotoxin receptor 1. Interacts with DNM2, DBNL, GRID2, BAIAP2, SLC9A3, PLCB3 and CFTR. Interacts (via proline-rich region) with PDE4D. Interacts with ABI1 (via SH3 domain).

Subcellular location. Apical cell membrane. Cytoplasm. Synapse. Postsynaptic density. Cell projection. Growth cone. Dendritic spine.

Tissue specificity. Isoform 3 is present in epithelial colonic cells (at protein level).

Disease relevance. Autism 17 (AUTS17) [MIM:613436] A complex multifactorial, pervasive developmental disorder characterized by impairments in reciprocal social interaction and communication, restricted and stereotyped patterns of interests and activities, and the presence of developmental abnormalities by 3 years of age. Most individuals with autism also manifest moderate intellectual disability. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Domain organisation. The PDZ domain is required for interaction with GRID2, PLCB3, CFTR and SLC9A3.

Miscellaneous. Contains 6 ANK repeats at positions 196-226, 230-259, 263-293, 297-326, 330-359, 363-393.

Similarity. Belongs to the SHANK family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9UPX8-3	3, E	yes
Q9UPX8-1	1, A
Q9UPX8-2	2, C
Q9UPX8-4	4, B

RefSeq proteins (3): NP_001366155, NP_036441, NP_573573 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001452	SH3_domain	Domain
IPR001478	PDZ	Domain
IPR001660	SAM	Domain
IPR002110	Ankyrin_rpt	Repeat
IPR013761	SAM/pointed_sf	Homologous_superfamily
IPR032425	FERM_f0	Domain
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR036034	PDZ_sf	Homologous_superfamily
IPR036770	Ankyrin_rpt-contain_sf	Homologous_superfamily
IPR041489	PDZ_6	Domain
IPR051569

Pfam: PF00536, PF07653, PF12796, PF16511, PF17820

UniProt features (60 total): compositionally biased region 18, region of interest 9, modified residue 7, helix 7, repeat 6, splice variant 5, domain 3, chain 1, short sequence motif 1, glycosylation site 1, sequence variant 1, turn 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
8B10	X-RAY DIFFRACTION	1.95
8ATJ	X-RAY DIFFRACTION	2.12

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UPX8-F1	52.58	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 (7): 831, 860, 960, 1099, 1278, 1709, 1713

Glycosylation sites (1): 1667

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-6794361	Neurexins and neuroligins
R-HSA-112316	Neuronal System
R-HSA-6794362	Protein-protein interactions at synapses

MSigDB gene sets: 250 (showing top): AAGCAAT_MIR137, GOBP_COGNITION, GOBP_BEHAVIOR, GOBP_SYNAPSE_ASSEMBLY, TGCACTT_MIR519C_MIR519B_MIR519A, GOBP_ADULT_BEHAVIOR, ATACCTC_MIR202, GOBP_ASSOCIATIVE_LEARNING, GOZGIT_ESR1_TARGETS_DN, GOBP_HIPPO_SIGNALING, chr11q13, RODWELL_AGING_KIDNEY_NO_BLOOD_DN, GOBP_CELL_CELL_SIGNALING, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GTGCCTT_MIR506

GO Biological Process (12): synapse assembly (GO:0007416), learning (GO:0007612), positive regulation of cell population proliferation (GO:0008284), associative learning (GO:0008306), adult behavior (GO:0030534), social behavior (GO:0035176), negative regulation of hippo signaling (GO:0035331), synapse organization (GO:0050808), long-term synaptic potentiation (GO:0060291), long-term synaptic depression (GO:0060292), vocalization behavior (GO:0071625), cognition (GO:0050890)

GO Molecular Function (4): SH3 domain binding (GO:0017124), synaptic receptor adaptor activity (GO:0030160), ionotropic glutamate receptor binding (GO:0035255), protein binding (GO:0005515)

GO Cellular Component (18): photoreceptor outer segment (GO:0001750), photoreceptor inner segment (GO:0001917), cytosol (GO:0005829), plasma membrane (GO:0005886), postsynaptic density (GO:0014069), apical plasma membrane (GO:0016324), growth cone (GO:0030426), brush border membrane (GO:0031526), neuron projection (GO:0043005), neuronal cell body (GO:0043025), dendritic spine (GO:0043197), ciliary membrane (GO:0060170), cytoplasm (GO:0005737), neurofilament (GO:0005883), membrane (GO:0016020), cell projection (GO:0042995), synapse (GO:0045202), postsynaptic membrane (GO:0045211)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Protein-protein interactions at synapses	1
Neuronal System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
behavior	3
regulation of synaptic plasticity	2
cytoplasm	2
cell projection membrane	2
postsynapse	2
nervous system development	1
cell junction assembly	1
synapse organization	1
learning or memory	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
learning	1
biological process involved in intraspecies interaction between organisms	1
hippo signaling	1
regulation of hippo signaling	1
negative regulation of intracellular signal transduction	1
cell junction organization	1
positive regulation of synaptic transmission	1
negative regulation of synaptic transmission	1
nervous system process	1
protein domain specific binding	1
signaling receptor complex adaptor activity	1
glutamate receptor binding	1
binding	1
photoreceptor cell cilium	1
membrane	1
cell periphery	1
asymmetric synapse	1
postsynaptic specialization	1
apical part of cell	1
plasma membrane region	1
site of polarized growth	1
distal axon	1
brush border	1
apical plasma membrane	1
plasma membrane bounded cell projection	1
somatodendritic compartment	1
cell body	1

Protein interactions and networks

STRING

1788 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SHANK2	DLG4	P78352	973
SHANK2	CTTN	Q14247	957
SHANK2	NLGN4X	Q8N0W4	929
SHANK2	DLGAP1	P78335	920
SHANK2	NLGN3	Q9NZ94	920
SHANK2	DLGAP2	Q9P1A6	915
SHANK2	HCLS1	P14317	900
SHANK2	HOMER1	Q86YM7	852
SHANK2	PTCHD1	Q96NR3	845
SHANK2	NLGN1	Q8N2Q7	831
SHANK2	NRXN1	Q9ULB1	826
SHANK2	CNTNAP2	Q9UHC6	813
SHANK2	SHARPIN	Q9H0F6	805
SHANK2	SYNGAP1	Q96PV0	804
SHANK2	SHANK3	Q9BYB0	800

IntAct

58 interactions, top by confidence:

A	B	Type	Score
PLCG1	SHANK2	psi-mi:“MI:0915”(physical association)	0.600
SHANK2	PLCG1	psi-mi:“MI:0407”(direct interaction)	0.600
SHANK2	PLCG1	psi-mi:“MI:0915”(physical association)	0.600
NLK	FAM222B	psi-mi:“MI:0914”(association)	0.530
BAIAP2L1	SHANK2	psi-mi:“MI:0407”(direct interaction)	0.440
SLC15A5	SHANK2	psi-mi:“MI:0407”(direct interaction)	0.440
ASIC3	SHANK2	psi-mi:“MI:0407”(direct interaction)	0.440
ABCC4	SHANK2	psi-mi:“MI:0407”(direct interaction)	0.440
SLCO1C1	SHANK2	psi-mi:“MI:0407”(direct interaction)	0.440
ORF putative E6	SHANK2	psi-mi:“MI:0407”(direct interaction)	0.440
TAMALIN	SHANK2	psi-mi:“MI:0407”(direct interaction)	0.440
ARHGEF16	SHANK2	psi-mi:“MI:0407”(direct interaction)	0.440
ATP2B4	SHANK2	psi-mi:“MI:0407”(direct interaction)	0.440
CYSLTR2	SHANK2	psi-mi:“MI:0407”(direct interaction)	0.440
DGKK	SHANK2	psi-mi:“MI:0407”(direct interaction)	0.440
DGKZ	SHANK2	psi-mi:“MI:0407”(direct interaction)	0.440
DOCK4	SHANK2	psi-mi:“MI:0407”(direct interaction)	0.440
FRMPD4	SHANK2	psi-mi:“MI:0407”(direct interaction)	0.440
FZD7	SHANK2	psi-mi:“MI:0407”(direct interaction)	0.440
E6	SHANK2	psi-mi:“MI:0407”(direct interaction)	0.440
KCNA5	SHANK2	psi-mi:“MI:0407”(direct interaction)	0.440
SHANK2	KIR3DL3	psi-mi:“MI:0407”(direct interaction)	0.440
MAP2K2	SHANK2	psi-mi:“MI:0407”(direct interaction)	0.440
PBK	SHANK2	psi-mi:“MI:0407”(direct interaction)	0.440
RALBP1	SHANK2	psi-mi:“MI:0407”(direct interaction)	0.440
RASSF6	SHANK2	psi-mi:“MI:0407”(direct interaction)	0.440
TJP2	SHANK2	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (74): CTTN (Two-hybrid), SHANK2 (Affinity Capture-MS), SHANK2 (Proximity Label-MS), SHANK2 (Affinity Capture-MS), SHANK2 (Affinity Capture-RNA), SHANK2 (Affinity Capture-RNA), SHANK2 (Two-hybrid), RET (Affinity Capture-Western), GRB10 (Affinity Capture-Western), SHANK2 (Affinity Capture-MS), SHANK2 (Reconstituted Complex), SHANK2 (Affinity Capture-Western), ARHGEF7 (Affinity Capture-Western), SHANK2 (Two-hybrid), SHANK2 (Two-hybrid)

ESM2 similar proteins: A0A0G2K2P5, A0JNJ1, B1WAP7, G9CGD6, O14640, O75122, O88382, O95049, O97758, P34908, P39447, P51141, P54792, P70175, Q05AS8, Q07157, Q16825, Q5F488, Q5IS48, Q5SGD7, Q5TCQ9, Q5XI81, Q61062, Q62136, Q62728, Q62936, Q6DKE2, Q6P9H4, Q6ZM86, Q812E4, Q86UL8, Q8BMA3, Q8IVH8, Q8JHI3, Q8TDW5, Q920B0, Q924I2, Q925T6, Q92997, Q95168

Diamond homologs: A0A096LNW5, A2RUV0, B4DH59, G3I6Z6, O35474, O35516, O75095, O89019, P07207, P0DPK3, P0DPK4, P13508, P20749, P21783, P31695, P46530, P46531, P82279, Q01705, Q04721, Q07008, Q20911, Q499M5, Q502K3, Q5RBP1, Q61982, Q6UXI9, Q6UY11, Q7Z3S9, Q810B6, Q8AVH7, Q8IUX8, Q91V88, Q99466, Q9FY48, Q9JJZ5, Q9P2R3, Q9QW30, Q9QXT5, Q9R172

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
SHANK2	“up-regulates activity”	ACTN1	relocalization
DLGAP1	“up-regulates activity”	SHANK2	relocalization
DLGAP2	“up-regulates activity”	SHANK2	relocalization
DLGAP3	“up-regulates activity”	SHANK2	relocalization
DLGAP4	“up-regulates activity”	SHANK2	relocalization
DLGAP5	“up-regulates activity”	SHANK2	relocalization
SHANK2	up-regulates	“Postsynaptic density assembly”
mir-137	“down-regulates quantity by destabilization”	SHANK2	“post transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 47 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
Downstream signal transduction	6	69.2×	9e-08
RAC1 GTPase cycle	5	9.2×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	21
Likely pathogenic	27
Uncertain significance	234
Likely benign	160
Benign	17

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1074590	NM_012309.5(SHANK2):c.2142del (p.Lys715fs)	Pathogenic
1177375	NM_012309.5(SHANK2):c.2593C>T (p.Gln865Ter)	Pathogenic
1184117	NM_012309.5(SHANK2):c.2207del (p.Pro736fs)	Pathogenic
1184866	NM_012309.5(SHANK2):c.2429C>G (p.Ser810Ter)	Pathogenic
1298530	GRCh37/hg19 11q13.4(chr11:70505933-70507872)x1	Pathogenic
1698936	NM_012309.5(SHANK2):c.4930G>T (p.Glu1644Ter)	Pathogenic
1708216	NM_012309.5(SHANK2):c.4749_4753del (p.Pro1584fs)	Pathogenic
1805933	NM_012309.5(SHANK2):c.4635_4636delinsTAT (p.Val1546fs)	Pathogenic
224127	NM_012309.5(SHANK2):c.1896dup (p.Asp633fs)	Pathogenic
2775433	NM_012309.5(SHANK2):c.4604del (p.Asp1535fs)	Pathogenic
3337614	NM_012309.5(SHANK2):c.2404_2420del (p.Ser802fs)	Pathogenic
3377203	NM_012309.5(SHANK2):c.553C>T (p.Arg185Ter)	Pathogenic
3377208	NM_012309.5(SHANK2):c.420C>G (p.Tyr140Ter)	Pathogenic
3391914	GRCh37/hg19 11q13.4(chr11:70410130-70605728)x1	Pathogenic
3897810	NM_012309.5(SHANK2):c.2374C>T (p.Pro792Ser)	Pathogenic
3900647	NM_012309.5(SHANK2):c.4371_4374del (p.Asn1458fs)	Pathogenic
4531318	NM_012309.5(SHANK2):c.1356del (p.Met453fs)	Pathogenic
4532180	NM_012309.5(SHANK2):c.2730_2737del (p.Lys910fs)	Pathogenic
562150	NM_012309.5(SHANK2):c.4304_4305del (p.Leu1434_Ser1435insTer)	Pathogenic
940365	NM_012309.5(SHANK2):c.2343del (p.Ser782fs)	Pathogenic
992847	NM_012309.5(SHANK2):c.2521C>T (p.Arg841Ter)	Pathogenic
1174489	NM_012309.5(SHANK2):c.1927G>A (p.Gly643Arg)	Likely pathogenic
1320184	NM_012309.5(SHANK2):c.2247dup (p.Lys750fs)	Likely pathogenic
1338535	NM_012309.5(SHANK2):c.1987C>T (p.Gln663Ter)	Likely pathogenic
1690890	NM_012309.5(SHANK2):c.4985_4986del (p.Pro1662fs)	Likely pathogenic
1803070	NM_012309.5(SHANK2):c.5176_5177del (p.Leu1726fs)	Likely pathogenic
1804793	NM_012309.5(SHANK2):c.1742del (p.Glu581fs)	Likely pathogenic
1807703	GRCh37/hg19 11q13.4(chr11:70517505-70807254)x1	Likely pathogenic
2584776	NM_012309.5(SHANK2):c.2198-1G>A	Likely pathogenic
2584777	NM_012309.5(SHANK2):c.2310dup (p.Lys771Ter)	Likely pathogenic

SpliceAI

5814 predictions. Top by Δscore:

Variant	Effect	Δscore
11:70487718:TTC:T	acceptor_gain	1.0000
11:70487719:TC:T	acceptor_gain	1.0000
11:70487720:CC:C	acceptor_gain	1.0000
11:70487721:C:CC	acceptor_gain	1.0000
11:70490384:CAGA:C	acceptor_gain	1.0000
11:70490388:C:CC	acceptor_gain	1.0000
11:70492333:A:AC	donor_gain	1.0000
11:70492334:C:CC	donor_gain	1.0000
11:70492334:CGTT:C	donor_gain	1.0000
11:70502199:GACTT:G	donor_loss	1.0000
11:70502200:ACTTA:A	donor_loss	1.0000
11:70502201:CTT:C	donor_loss	1.0000
11:70502202:TTA:T	donor_loss	1.0000
11:70502203:TA:T	donor_loss	1.0000
11:70502204:A:AC	donor_gain	1.0000
11:70502205:C:CC	donor_gain	1.0000
11:70502205:CCGAG:C	donor_gain	1.0000
11:70502282:GGGAG:G	acceptor_gain	1.0000
11:70502283:GGAG:G	acceptor_gain	1.0000
11:70502284:GAG:G	acceptor_gain	1.0000
11:70502284:GAGC:G	acceptor_loss	1.0000
11:70502285:AG:A	acceptor_gain	1.0000
11:70502287:C:CC	acceptor_gain	1.0000
11:70502791:TGTAC:T	donor_loss	1.0000
11:70502792:GTACC:G	donor_loss	1.0000
11:70502793:TACC:T	donor_loss	1.0000
11:70502794:A:AC	donor_gain	1.0000
11:70502794:ACCT:A	donor_loss	1.0000
11:70502795:C:CC	donor_gain	1.0000
11:70502795:CCTTT:C	donor_gain	1.0000

AlphaMissense

12114 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:70472960:A:G	L1441P	1.000
11:70472969:A:G	L1438S	1.000
11:70473035:A:G	L1416P	1.000
11:70473063:A:G	W1407R	1.000
11:70473063:A:T	W1407R	1.000
11:70659895:A:G	L286P	1.000
11:70659912:G:C	F280L	1.000
11:70659912:G:T	F280L	1.000
11:70659914:A:G	F280L	1.000
11:70659930:G:C	F274L	1.000
11:70659930:G:T	F274L	1.000
11:70659931:A:G	F274S	1.000
11:70659932:A:G	F274L	1.000
11:70661610:A:G	L262P	1.000
11:70661610:A:T	L262H	1.000
11:70661616:A:G	F260S	1.000
11:70798496:A:G	F196S	1.000
11:70798500:A:G	W195R	1.000
11:70798500:A:T	W195R	1.000
11:70798524:C:G	G187R	1.000
11:70807007:A:T	V174D	1.000
11:70472911:T:A	R1457S	0.999
11:70472911:T:G	R1457S	0.999
11:70472918:C:T	G1455E	0.999
11:70472919:C:A	G1455W	0.999
11:70472919:C:G	G1455R	0.999
11:70472919:C:T	G1455R	0.999
11:70472924:C:G	R1453P	0.999
11:70472930:A:T	V1451E	0.999
11:70472936:A:G	L1449P	0.999

dbSNP variants (sampled 300 via entrez): RS1000001297 (11:71090703 C>T), RS1000008210 (11:70601868 G>A), RS1000009039 (11:70569206 C>T), RS1000015040 (11:70926879 G>A), RS1000020634 (11:71062664 A>G), RS1000021158 (11:70565504 C>T), RS1000031002 (11:70742368 G>T), RS1000046354 (11:70539418 C>T), RS1000048338 (11:71103604 C>A), RS1000054331 (11:70711210 C>A,T), RS1000059751 (11:70780005 A>C,G,T), RS1000067142 (11:70744826 G>A,C), RS1000071004 (11:70673640 G>A), RS1000073056 (11:70639267 T>G), RS1000083758 (11:70711364 G>T)

Disease associations

OMIM: gene MIM:603290 | disease phenotypes: MIM:613436, MIM:209850, MIM:181500

GenCC curated gene-disease

Disease	Classification	Inheritance
autism, susceptibility to, 17	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Definitive	AD

Mondo (7): intellectual disability (MONDO:0001071), autism, susceptibility to, 17 (MONDO:0013265), autism spectrum disorder (MONDO:0005258), neurodevelopmental disorder (MONDO:0700092), autism (MONDO:0005260), complex neurodevelopmental disorder (MONDO:0100038), schizophrenia (MONDO:0005090)

Orphanet (5): Rare disease with autism (Orphanet:180772), Non-specific syndromic intellectual disability (Orphanet:528084), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Autism (Orphanet:106), NON RARE IN EUROPE: Schizophrenia (Orphanet:3140)

HPO phenotypes

2 total (2 of 2 shown, HPO-id order):

HPO	Term
HP:0000717	Autism
HP:0100753	Schizophrenia

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST001738_2	Response to fenofibrate (adiponectin levels)	3.000000e-06
GCST001762_107	Obesity-related traits	1.000000e-06
GCST002828_12	Urate levels in obese individuals	9.000000e-06
GCST003815_118	Late-onset Alzheimer’s disease	8.000000e-06
GCST008103_16	Bipolar disorder	8.000000e-09
GCST008162_4	Hip circumference	2.000000e-06
GCST010396_183	Gut microbiota (bacterial taxa, hurdle binary method)	3.000000e-06
GCST012335_25	Hodgkin’s lymphoma	4.000000e-11
GCST012465_9	Bipolar disorder	1.000000e-10
GCST90014243_7	Kawasaki disease	6.000000e-07
GCST90027899_8	Eosinophilic esophagitis	1.000000e-09

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004697	estradiol measurement
EFO:0004531	urate measurement
EFO:1001870	late-onset Alzheimers disease
EFO:0007874	gut microbiome measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects expression, affects methylation, decreases expression	9
Valproic Acid	increases methylation, affects cotreatment, increases expression, affects expression	8
Aflatoxin B1	affects expression, affects methylation, decreases expression, decreases methylation	6
methylmercuric chloride	increases expression, affects cotreatment	3
trichostatin A	affects cotreatment, increases expression	3
Tretinoin	decreases expression, increases expression	3
Cyclosporine	decreases expression	3
bisphenol A	affects methylation, decreases expression	2
bisphenol S	decreases expression, decreases methylation	2
Cisplatin	affects cotreatment, decreases expression, decreases reaction, decreases response to substance	2
Nickel	decreases expression	2
Silicon Dioxide	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
dicrotophos	increases expression	1
methyleugenol	decreases expression	1
propionaldehyde	increases expression	1
afimoxifene	increases expression	1
11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid	affects methylation, increases abundance	1
fenvalerate	decreases expression	1
sodium arsenite	increases expression	1
ochratoxin A	decreases expression	1
benzo(e)pyrene	affects methylation	1
aflatoxin B2	decreases methylation	1
nickel sulfate	decreases expression	1
fumonisin B1	decreases expression	1
glycidamide	decreases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	affects cotreatment, decreases expression	1

Cellosaurus cell lines

2 cell lines: 2 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A1QI	UKHGi003-A	Induced pluripotent stem cell	Female
CVCL_A1QJ	UKHGi003-B	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT01302964	PHASE3	COMPLETED	Mirtazapine Treatment of Anxiety in Children and Adolescents With Pervasive Developmental Disorders
NCT01706523	PHASE3	TERMINATED	Open Label Extension Study of STX209 (Arbaclofen) in Autism Spectrum Disorders
NCT01825798	PHASE3	COMPLETED	Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism Spectrum Disorders (ASD)
NCT01972074	PHASE3	COMPLETED	Behavioral and Neural Response to Memantine in Adolescents With Autism Spectrum Disorder
NCT02985749	PHASE3	COMPLETED	A Study of Oxytocin for the Treatment of Social Impairment in Individuals With High Functioning Autism Spectrum Disorder
NCT03197922	PHASE3	COMPLETED	Treatment of Encopresis in Children With Autism Spectrum Disorders
NCT03504917	PHASE3	TERMINATED	A Study of Balovaptan in Adults With Autism Spectrum Disorder With a 2-Year Open-Label Extension
NCT03553875	PHASE3	TERMINATED	Memantine for the Treatment of Social Deficits in Youth With Disorders of Impaired Social Interactions
NCT03640156	PHASE3	COMPLETED	Modulating Socially Adaptive Mirror System Functioning in Autism by Oxytocin
NCT03715153	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children Aged From 2 to Less Than 7 Years Old With Autism Spectrum Disorder.
NCT03715166	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children and Adolescents Aged From 7 to Less Than 18 Years Old With Autism Spectrum Disorder
NCT04233502	PHASE3	WITHDRAWN	Efficacy and Safety of Slenyto for Insomnia in Children With ASD
NCT04578756	PHASE3	COMPLETED	Open-Label, Flexible-dose Study to Evaluate the Long-Term Safety and Tolerability of Cariprazine in the Treatment of Pediatric Participants With Schizophrenia, Bipolar I Disorder, or Autism Spectrum Disorder
NCT04623398	PHASE3	COMPLETED	Effect of Lithium in Patients With Autism Spectrum Disorder and Phelan-McDermid Syndrome (SHANK3 Haploinsufficiency)