SHANK1

Summary

SHANK1 (SH3 and multiple ankyrin repeat domains 1, HGNC:15474) is a protein-coding gene on chromosome 19q13.33, encoding SH3 and multiple ankyrin repeat domains protein 1 (Q9Y566). 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 via complexes with GKAP/PSD-95 and Homer, respectively, and the actin-based….

This gene encodes a member of the SHANK (SH3 domain and ankyrin repeat containing) family of proteins. Members of this family act as scaffold proteins that are required for the development and function of neuronal synapses. Deletions in this gene may be associated with autism spectrum disorder in males.

Source: NCBI Gene 50944 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 4
• Clinical variants (ClinVar): 611 total — 11 pathogenic, 7 likely-pathogenic
• Dosage sensitivity (ClinGen): haploinsufficiency little evidence, triplosensitivity no evidence
• MANE Select transcript: NM_016148

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15474
Approved symbol	SHANK1
Name	SH3 and multiple ankyrin repeat domains 1
Location	19q13.33
Locus type	gene with protein product
Status	Approved
Aliases	SSTRIP, SPANK-1, synamon
Ensembl gene	ENSG00000161681
Ensembl biotype	protein_coding
OMIM	604999
Entrez	50944

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 5 protein_coding, 3 retained_intron, 1 nonsense_mediated_decay

ENST00000293441, ENST00000359082, ENST00000391813, ENST00000391814, ENST00000461154, ENST00000468654, ENST00000483128, ENST00000850966, ENST00000850967

RefSeq mRNA: 1 — MANE Select: NM_016148 NM_016148

CCDS: CCDS12799

Canonical transcript exons

ENST00000293441 — 24 exons

Exon	Start	End
ENSE00001059673	50704120	50704186
ENSE00001059674	50716275	50716478
ENSE00001059676	50697096	50697122
ENSE00001059682	50714182	50714290
ENSE00001059685	50715659	50715730
ENSE00001059689	50711371	50711487
ENSE00001059696	50704437	50704514
ENSE00001116524	50687923	50688058
ENSE00001116528	50702467	50702660
ENSE00001116531	50686744	50686812
ENSE00001116534	50686237	50686355
ENSE00001116535	50672018	50672114
ENSE00001124209	50666192	50669285
ENSE00001124231	50687582	50687662
ENSE00001124248	50688844	50688968
ENSE00001124254	50689197	50689279
ENSE00001124264	50697589	50697664
ENSE00001124269	50697843	50697956
ENSE00001124283	50703500	50703830
ENSE00001124310	50713798	50713949
ENSE00001509806	50716665	50716962
ENSE00003494296	50711947	50712114
ENSE00003906879	50659255	50662682
ENSE00003908894	50719406	50719802

Expression profiles

Bgee: expression breadth ubiquitous, 183 present calls, max score 95.03.

FANTOM5 (CAGE): breadth broad, TPM avg 2.0993 / max 122.0517, expressed in 522 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
182264	1.7267	481
182254	0.1491	67
182255	0.1274	57
182263	0.0341	15
182265	0.0327	14
182256	0.0292	19

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
anterior cingulate cortex	UBERON:0009835	95.03	gold quality
cingulate cortex	UBERON:0003027	94.94	gold quality
right frontal lobe	UBERON:0002810	93.66	gold quality
prefrontal cortex	UBERON:0000451	93.51	gold quality
amygdala	UBERON:0001876	92.57	gold quality
right hemisphere of cerebellum	UBERON:0014890	91.84	gold quality
neocortex	UBERON:0001950	91.31	gold quality
frontal cortex	UBERON:0001870	91.06	gold quality
cerebellar cortex	UBERON:0002129	90.93	gold quality
cerebellar hemisphere	UBERON:0002245	90.85	gold quality
primary visual cortex	UBERON:0002436	89.77	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	89.76	gold quality
cortical plate	UBERON:0005343	89.63	gold quality
cerebellum	UBERON:0002037	89.60	gold quality
cerebral cortex	UBERON:0000956	89.39	gold quality
Brodmann (1909) area 9	UBERON:0013540	88.95	gold quality
temporal lobe	UBERON:0001871	88.85	gold quality
Ammon’s horn	UBERON:0001954	88.37	gold quality
middle temporal gyrus	UBERON:0002771	86.52	gold quality
hypothalamus	UBERON:0001898	86.07	gold quality
superior frontal gyrus	UBERON:0002661	85.71	gold quality
telencephalon	UBERON:0001893	85.40	gold quality
stromal cell of endometrium	CL:0002255	85.15	gold quality
forebrain	UBERON:0001890	84.80	gold quality
entorhinal cortex	UBERON:0002728	84.74	gold quality
brain	UBERON:0000955	84.71	gold quality
occipital lobe	UBERON:0002021	83.97	gold quality
Brodmann (1909) area 23	UBERON:0013554	83.23	gold quality
nucleus accumbens	UBERON:0001882	83.13	gold quality
orbitofrontal cortex	UBERON:0004167	82.40	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	2.94

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NR1I2

miRNA regulators (miRDB)

146 targeting SHANK1, 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-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-4745-5P	99.98	65.95	1028
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-1468-3P	99.96	72.74	3797
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-3658	99.96	73.87	4379

Functional genomics

ClinGen dosage: haploinsufficiency 1 (little evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 12)

• Results show that dendritic targeting of shank1 mRNA granules involves KIF5C and the KIF5-associated RNA-binding protein staufen1. (PMID:19416473)
• The results of this study suggested a role of SHANK1 in working memory deficits in schizophrenia. (PMID:21901269)
• A hemizygous SHANK1 deletion segregates in a four-generation family in which male carriers–but not female carriers–have autism spectrum disorder with higher functioning. (PMID:22503632)
• a non-canonical initiation site is required for efficient translation of the dendritically localized Shank1 mRNA (PMID:24533096)
• Data show that the Shank1 protein mRNA 3’ UTR adopts two very stable intramolecular G-quadruplexes which are bound specifically and with high affinity by X mental retardation protein (FMRP). (PMID:25692235)
• SHANK1 and SHANK3 act as integrin activation inhibitors by sequestering active Rap1 and R-Ras via the SPN domain and thus limiting their bioavailability at the plasma membrane. (PMID:28263956)
• Authors summarize and discuss behavioral and neuronal findings obtained in the Shank1 knockout mouse model for Autism spectrum disorder (ASD); identify open research questions by comparing such findings with the symptoms present in humans diagnosed with ASD and carrying SHANK1 deletions; conclude by discussing the implications of the behavioral and neuronal phenotypes displayed by the Shank1 knockout mouse model. (PMID:28963042)
• SH3 and multiple ankyrin repeat domains protein (SHANK) family includes the three multidomain structural proteins (SHANK1, SHANK2, and SHANK3) that enrich in excitatory glutamatergic synapses in mammalian brain. (PMID:30629339)
• The roles of SHANK1 in the development of colon cancer. (PMID:32356303)
• Dynamic Change of Shanks Gene mRNA Expression and DNA Methylation in Epileptic Rat Model and Human Patients. (PMID:32564287)
• Truncating variants in the SHANK1 gene are associated with a spectrum of neurodevelopmental disorders. (PMID:34113010)
• A recurrent SHANK1 mutation implicated in autism spectrum disorder causes autistic-like core behaviors in mice via downregulation of mGluR1-IP3R1-calcium signaling. (PMID:35388181)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	shank1	ENSDARG00000060539
mus_musculus	Shank1	ENSMUSG00000038738
rattus_norvegicus	Shank1	ENSRNOG00000019207
drosophila_melanogaster	Prosap	FBGN0040752
caenorhabditis_elegans		WBGENE00006444

Paralogs (2): SHANK2 (ENSG00000162105), SHANK3 (ENSG00000251322)

Protein

Protein identifiers

SH3 and multiple ankyrin repeat domains protein 1 — Q9Y566 (reviewed: Q9Y566)

Alternative names: Somatostatin receptor-interacting protein

All UniProt accessions (3): Q9Y566, H9KV90, M0QYB5

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 via complexes with GKAP/PSD-95 and Homer, respectively, and the actin-based cytoskeleton. Plays a role in the structural and functional organization of the dendritic spine and synaptic junction.

Subunit / interactions. May homomultimerize via its SAM domain. Interacts with the C-terminus of SSTR2 via the PDZ domain. Interacts with IGSF9, SHARPIN, SPTAN1, HOMER1 and DLGAP1/GKAP isoforms 1 and 2. Part of a complex with DLG4/PSD-95 and DLGAP1/GKAP. Interacts with BAIAP2. Interacts with HOMER1 and HOMER3.

Subcellular location. Cytoplasm. Postsynaptic density. Synapse.

Tissue specificity. Expressed in brain particularly in the amygdala, hippocampus, substantia nigra and thalamus. Isoform 2 seems to be expressed ubiquitously.

Similarity. Belongs to the SHANK family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9Y566-1	1, A	yes
Q9Y566-2	2, B
Q9Y566-3	3

RefSeq proteins (1): NP_057232* (*=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
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, PF17820

UniProt features (92 total): compositionally biased region 25, modified residue 18, region of interest 11, strand 11, repeat 6, sequence conflict 6, sequence variant 4, splice variant 3, domain 3, helix 3, chain 1, turn 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
6YX0	X-RAY DIFFRACTION	1.57
6YX2	X-RAY DIFFRACTION	1.62
7A00	X-RAY DIFFRACTION	1.78
6YX1	X-RAY DIFFRACTION	1.8
8S1R	X-RAY DIFFRACTION	1.98
6YWZ	X-RAY DIFFRACTION	2.12
6CPI	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y566-F1	48.59	0.15

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 (18): 186, 540, 544, 671, 791, 890, 950, 1051, 1090, 1101, 1253, 1287, 1423, 1436, 1895, 2016, 2036, 2074

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: 193 (showing top): GOBP_DENDRITE_DEVELOPMENT, GOBP_MEMORY, RNGTGGGC_UNKNOWN, GOBP_ACTIN_FILAMENT_BUNDLE_ORGANIZATION, GOBP_COGNITION, GOBP_BEHAVIOR, GOBP_ADULT_BEHAVIOR, GOBP_ASSOCIATIVE_LEARNING, GOBP_DENDRITIC_SPINE_DEVELOPMENT, GOBP_CELLULAR_COMPONENT_MAINTENANCE, GOBP_NEUROGENESIS, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_REFLEX, GOBP_NEUROMUSCULAR_PROCESS_CONTROLLING_BALANCE, EFC_Q6

GO Biological Process (24): long-term memory (GO:0007616), associative learning (GO:0008306), adult behavior (GO:0030534), negative regulation of actin filament bundle assembly (GO:0032232), social behavior (GO:0035176), protein localization to synapse (GO:0035418), olfactory behavior (GO:0042048), habituation (GO:0046959), synapse organization (GO:0050808), neuromuscular process controlling balance (GO:0050885), determination of affect (GO:0050894), righting reflex (GO:0060013), synapse maturation (GO:0060074), dendritic spine morphogenesis (GO:0060997), positive regulation of dendritic spine development (GO:0060999), protein-containing complex assembly (GO:0065003), vocalization behavior (GO:0071625), AMPA selective glutamate receptor signaling pathway (GO:0098990), positive regulation of excitatory postsynaptic potential (GO:2000463), nervous system development (GO:0007399), cell differentiation (GO:0030154), modulation of chemical synaptic transmission (GO:0050804), cognition (GO:0050890), maintenance of postsynaptic density structure (GO:0099562)

GO Molecular Function (12): SH3 domain binding (GO:0017124), synaptic receptor adaptor activity (GO:0030160), somatostatin receptor binding (GO:0031877), ionotropic glutamate receptor binding (GO:0035255), identical protein binding (GO:0042802), protein-containing complex binding (GO:0044877), ankyrin repeat binding (GO:0071532), scaffold protein binding (GO:0097110), structural constituent of postsynaptic density (GO:0098919), G protein-coupled receptor binding (GO:0001664), protein binding (GO:0005515), signaling receptor complex adaptor activity (GO:0030159)

GO Cellular Component (13): cytosol (GO:0005829), plasma membrane (GO:0005886), postsynaptic density (GO:0014069), membrane (GO:0016020), dendrite (GO:0030425), neuron projection (GO:0043005), dendritic spine (GO:0043197), postsynaptic membrane (GO:0045211), excitatory synapse (GO:0060076), Schaffer collateral - CA1 synapse (GO:0098685), glutamatergic synapse (GO:0098978), cytoplasm (GO:0005737), synapse (GO:0045202)

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
behavior	3
cellular anatomical structure	3
synapse	3
dendritic spine development	2
protein domain specific binding	2
protein binding	2
binding	2
signaling receptor binding	2
postsynapse	2
memory	1
learning	1
regulation of actin filament bundle assembly	1
actin filament bundle assembly	1
negative regulation of cytoskeleton organization	1
negative regulation of supramolecular fiber organization	1
biological process involved in intraspecies interaction between organisms	1
protein localization to cell junction	1
chemosensory behavior	1
nonassociative learning	1
cell junction organization	1
musculoskeletal movement	1
neuromuscular process	1
sensory processing	1
reflex	1
nervous system development	1
developmental maturation	1
synapse organization	1
neuron projection development	1
neuron projection morphogenesis	1
dendrite morphogenesis	1
dendritic spine organization	1
positive regulation of developmental process	1
regulation of dendritic spine development	1
cellular component assembly	1
protein-containing complex organization	1
AMPA glutamate receptor activity	1
ionotropic glutamate receptor signaling pathway	1
positive regulation of signal transduction	1
excitatory postsynaptic potential	1
modulation of excitatory postsynaptic potential	1

Protein interactions and networks

STRING

3138 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SHANK1	DLGAP1	P78335	975
SHANK1	DLG4	P78352	974
SHANK1	HOMER1	Q86YM7	950
SHANK1	HOMER3	Q9NSC5	917
SHANK1	HCLS1	P14317	861
SHANK1	GRM5	P41594	853
SHANK1	CTTN	Q14247	844
SHANK1	NLGN1	Q8N2Q7	837
SHANK1	HOMER2	Q9NSB8	836
SHANK1	NLGN3	Q9NZ94	787
SHANK1	NLGN4X	Q8N0W4	776
SHANK1	GRM1	Q13255	760
SHANK1	NRXN1	Q9ULB1	754
SHANK1	SYNGAP1	Q96PV0	747
SHANK1	SPTAN1	Q13813	731

IntAct

418 interactions, top by confidence:

A	B	Type	Score
SHANK1	ACE2	psi-mi:“MI:0915”(physical association)	0.720
ACE2	SHANK1	psi-mi:“MI:0407”(direct interaction)	0.720
SHANK1	MCC	psi-mi:“MI:0407”(direct interaction)	0.620
SHANK1	WWTR1	psi-mi:“MI:0407”(direct interaction)	0.620
SHANK1	YAP1	psi-mi:“MI:0407”(direct interaction)	0.620
YAP1	SHANK1	psi-mi:“MI:0407”(direct interaction)	0.620
WWTR1	SHANK1	psi-mi:“MI:0407”(direct interaction)	0.620
MCC	SHANK1	psi-mi:“MI:0407”(direct interaction)	0.620
SHANK1	RPS6KA2	psi-mi:“MI:0407”(direct interaction)	0.560
SHANK1	LRRC7	psi-mi:“MI:0915”(physical association)	0.490
BAIAP2L1	SHANK1	psi-mi:“MI:0407”(direct interaction)	0.440
SHANK1	TBC1D10C	psi-mi:“MI:0407”(direct interaction)	0.440
SHANK1	TMEM219	psi-mi:“MI:0407”(direct interaction)	0.440
SHANK1	SLC26A6	psi-mi:“MI:0407”(direct interaction)	0.440
SHANK1	VEPH1	psi-mi:“MI:0407”(direct interaction)	0.440
SHANK1	rep	psi-mi:“MI:0407”(direct interaction)	0.440
SHANK1		psi-mi:“MI:0407”(direct interaction)	0.440
SHANK1	P/V	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (49): SHANK1 (Two-hybrid), SHANK1 (Affinity Capture-MS), SHANK1 (Biochemical Activity), DLGAP1 (Co-crystal Structure), SHANK1 (Co-crystal Structure), SHANK1 (Affinity Capture-MS), ARHGEF7 (Affinity Capture-Western), ARHGEF7 (Reconstituted Complex), BAIAP2 (Two-hybrid), SHANK1 (Far Western), SHANK1 (Affinity Capture-Western), SHANK1 (Two-hybrid), Sstr2 (Affinity Capture-Western), Sstr2 (Far Western), BAIAP2 (Affinity Capture-Western)

ESM2 similar proteins: A0A8P0N4K0, A2AB59, B4F7F3, D3YZU1, D3ZD05, O35681, O75427, O95382, P22455, P22607, P40748, P55144, P70218, Q06418, Q14160, Q1LZH7, Q2PS20, Q32P44, Q495M9, Q4ACU6, Q4H4B6, Q505F5, Q5F488, Q61851, Q63ZY3, Q6P9K8, Q6TLK4, Q6ZUM4, Q7KRY7, Q80T11, Q80U72, Q8BH60, Q8BX02, Q8N1G4, Q8TE68, Q8VC03, Q8VHK1, Q8VHK2, Q8WXD9, Q8WXE0

Diamond homologs: A0A8C0NGY6, A1A5G4, A1CQG2, A1D3C5, A2QQ28, A7UA95, B0XQ72, B8N7E5, D3YZU1, D6C652, G0S9J5, H2LBU8, O14326, O14910, O34328, O88382, O88951, O88952, P15454, P39940, P46934, P46935, P46937, P46938, P57105, P57888, P65220, P65221, P72648, Q0CCL1, Q0I868, Q0P5F3, Q110R6, Q12IL8, Q182S8, Q1GH67, Q1L8J7, Q28C55, Q2EJA0, Q2JQ59

SIGNOR signaling

11 interactions.

A	Effect	B	Mechanism
HOMER1	“up-regulates activity”	SHANK1	binding
SHANK1	“up-regulates activity”	ACTN1	relocalization
DLGAP1	“up-regulates activity”	SHANK1	relocalization
DLGAP2	“up-regulates activity”	SHANK1	relocalization
DLGAP3	“up-regulates activity”	SHANK1	relocalization
DLGAP4	“up-regulates activity”	SHANK1	relocalization
DLGAP5	“up-regulates activity”	SHANK1	relocalization
SHANK1	up-regulates	“Postsynaptic density assembly”
HOMER	“up-regulates activity”	SHANK1	binding
FUS	“up-regulates quantity”	SHANK1	“post transcriptional regulation”
FMR1	“up-regulates quantity”	SHANK1	“post transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 177 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
Neurexins and neuroligins	6	9.8×	3e-03
Cell death signalling via NRAGE, NRIF and NADE	5	9.1×	9e-03
R-HSA-425366	6	9.0×	3e-03
G alpha (12/13) signalling events	6	6.8×	9e-03
RHO GTPase cycle	13	6.5×	3e-05
SLC-mediated transmembrane transport	13	6.4×	3e-05
CDC42 GTPase cycle	10	6.0×	1e-03
RAC1 GTPase cycle	9	4.5×	7e-03

GO biological processes:

GO term	Partners	Fold	FDR
regulation of cardiac conduction	5	26.3×	2e-04
obsolete organic anion transport	5	25.1×	3e-04
positive regulation of synaptic transmission, glutamatergic	5	19.5×	8e-04
positive regulation of excitatory postsynaptic potential	5	16.5×	1e-03
adult behavior	5	14.6×	2e-03
synapse organization	8	14.0×	4e-05
regulation of G protein-coupled receptor signaling pathway	5	11.7×	6e-03
monoatomic ion transport	11	10.7×	9e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	11
Likely pathogenic	7
Uncertain significance	434
Likely benign	114
Benign	29

Top pathogenic / likely-pathogenic (18)

Variant ID	HGVS	Classification
1311170	NM_016148.5(SHANK1):c.2137C>T (p.Arg713Ter)	Pathogenic
1676868	NM_016148.5(SHANK1):c.1198C>T (p.Arg400Ter)	Pathogenic
2198098	NM_016148.5(SHANK1):c.1776G>A (p.Trp592Ter)	Pathogenic
2662531	NM_016148.5(SHANK1):c.4407del (p.His1470fs)	Pathogenic
2684892	GRCh37/hg19 19q13.33-13.43(chr19:49625130-57647352)x3	Pathogenic
3795502	NM_016148.5(SHANK1):c.4663del (p.Asp1555fs)	Pathogenic
3795503	NM_016148.5(SHANK1):c.1207C>T (p.Arg403Ter)	Pathogenic
3907791	NM_016148.5(SHANK1):c.5531dup (p.Pro1847fs)	Pathogenic
4531737	NM_016148.5(SHANK1):c.1366del (p.Ala456fs)	Pathogenic
4630827	NM_016148.5(SHANK1):c.3894C>A (p.Tyr1298Ter)	Pathogenic
4813351	NM_016148.5(SHANK1):c.3595_3599del (p.Ser1199fs)	Pathogenic
1708219	NM_016148.5(SHANK1):c.1882_1883del (p.Lys628fs)	Likely pathogenic
2505180	NM_016148.5(SHANK1):c.733C>T (p.Arg245Trp)	Likely pathogenic
3037192	NM_016148.5(SHANK1):c.2397delinsAA (p.Gln800fs)	Likely pathogenic
3376868	NM_016148.5(SHANK1):c.4337_4343dup (p.Thr1451fs)	Likely pathogenic
3897636	NM_016148.5(SHANK1):c.4714G>T (p.Glu1572Ter)	Likely pathogenic
3900654	NM_016148.5(SHANK1):c.2741_2742del (p.Val914fs)	Likely pathogenic
4074881	NM_016148.5(SHANK1):c.5709del (p.Asp1903fs)	Likely pathogenic

SpliceAI

3832 predictions. Top by Δscore:

Variant	Effect	Δscore
19:50672130:C:CT	acceptor_gain	1.0000
19:50672131:A:T	acceptor_gain	1.0000
19:50686356:C:CC	acceptor_gain	1.0000
19:50686362:G:C	acceptor_gain	1.0000
19:50686362:G:GC	acceptor_gain	1.0000
19:50686742:A:AC	donor_gain	1.0000
19:50686743:C:CC	donor_gain	1.0000
19:50686811:CT:C	acceptor_gain	1.0000
19:50686813:C:CC	acceptor_gain	1.0000
19:50687577:CTCA:C	donor_loss	1.0000
19:50687578:TCA:T	donor_loss	1.0000
19:50687579:CACCC:C	donor_loss	1.0000
19:50687580:A:AC	donor_gain	1.0000
19:50687580:A:C	donor_loss	1.0000
19:50687580:AC:A	donor_gain	1.0000
19:50687581:C:CC	donor_gain	1.0000
19:50687581:CC:C	donor_gain	1.0000
19:50687581:CCCAT:C	donor_gain	1.0000
19:50687584:ATCT:A	donor_gain	1.0000
19:50687585:T:C	donor_gain	1.0000
19:50687659:GGTG:G	acceptor_gain	1.0000
19:50687660:GTG:G	acceptor_gain	1.0000
19:50687661:TG:T	acceptor_gain	1.0000
19:50687661:TGCTG:T	acceptor_loss	1.0000
19:50687663:C:CC	acceptor_gain	1.0000
19:50687663:CTGAA:C	acceptor_loss	1.0000
19:50688840:TGAC:T	donor_loss	1.0000
19:50688841:GAC:G	donor_loss	1.0000
19:50688843:C:A	donor_loss	1.0000
19:50688843:CCT:C	donor_gain	1.0000

AlphaMissense

13751 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:50661987:A:G	L2155P	1.000
19:50661993:C:G	R2153P	1.000
19:50661999:A:T	I2151N	1.000
19:50662008:C:G	R2148P	1.000
19:50662009:G:T	R2148S	1.000
19:50662014:C:T	G2146D	1.000
19:50662032:A:G	L2140P	1.000
19:50662056:A:G	L2132S	1.000
19:50662065:A:G	L2129P	1.000
19:50662074:C:T	G2126D	1.000
19:50662094:G:C	F2119L	1.000
19:50662094:G:T	F2119L	1.000
19:50662095:A:C	F2119C	1.000
19:50662095:A:G	F2119S	1.000
19:50662096:A:G	F2119L	1.000
19:50662131:A:G	L2107P	1.000
19:50662135:A:G	W2106R	1.000
19:50662135:A:T	W2106R	1.000
19:50662157:C:A	W2098C	1.000
19:50662157:C:G	W2098C	1.000
19:50662158:C:G	W2098S	1.000
19:50662159:A:G	W2098R	1.000
19:50662159:A:T	W2098R	1.000
19:50666339:A:G	L1874P	1.000
19:50666339:A:T	L1874H	1.000
19:50666351:A:T	I1870N	1.000
19:50668487:A:C	I1158S	1.000
19:50668487:A:G	I1158T	1.000
19:50668487:A:T	I1158N	1.000
19:50686328:G:T	A829D	1.000

dbSNP variants (sampled 300 via entrez): RS1000003649 (19:50709712 G>A,C), RS1000034865 (19:50709433 G>A), RS1000172678 (19:50715523 G>A), RS1000203099 (19:50673660 C>T), RS1000365893 (19:50683070 G>A,T), RS1000420672 (19:50687865 T>G), RS1000524532 (19:50687507 C>A,G,T), RS1000671942 (19:50715192 T>C), RS1000782173 (19:50695411 G>A,C,T), RS1000783332 (19:50659944 C>T), RS1000797490 (19:50664075 G>C), RS1000799096 (19:50682724 A>G), RS1000844562 (19:50700598 G>A), RS1000889492 (19:50663606 G>A), RS1000957761 (19:50705967 G>A)

Disease associations

OMIM: gene MIM:604999 | disease phenotypes: MIM:192350

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder	Strong	Autosomal dominant
autism	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), neurodevelopmental disorder (MONDO:0700092), hearing loss disorder (MONDO:0005365), complex neurodevelopmental disorder (MONDO:0100038), VACTERL/vater association (MONDO:0008642), multiple congenital anomalies/dysmorphic syndrome (MONDO:0019042), autism (MONDO:0005260)

Orphanet (4): Non-specific syndromic intellectual disability (Orphanet:528084), VACTERL/VATER association (Orphanet:887), Multiple congenital anomalies/dysmorphic syndrome (Orphanet:68341), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST002777_9	Clozapine-induced cytotoxicity	9.000000e-06
GCST010536_5	Carotid plaque maximum area	5.000000e-06
GCST010538_6	Sum of carotid plaque area	2.000000e-07
GCST010539_7	Sum of stenosis	3.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0006952	cytotoxicity measurement
EFO:0006501	carotid plaque build

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
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

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases methylation	2
aristolochic acid I	increases expression	1
ethylbenzene	affects cotreatment, decreases expression	1
bisphenol A	affects cotreatment, increases methylation	1
ethyl-p-hydroxybenzoate	decreases expression	1
sodium arsenite	affects methylation	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
abrine	increases expression	1
(+)-JQ1 compound	decreases expression	1
Sunitinib	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Acetaminophen	decreases expression	1
Air Pollutants	increases expression, increases abundance	1
Diazinon	increases methylation	1
Lead	affects methylation	1
Methapyrilene	increases methylation	1
Dronabinol	decreases expression	1
Thiram	increases expression	1
Toluene	affects cotreatment, decreases expression	1
Triclosan	increases expression	1
Xylenes	affects cotreatment, decreases expression	1
Aflatoxin B1	decreases expression	1
Paclitaxel	affects response to substance	1
Okadaic Acid	increases expression	1
Particulate Matter	increases abundance, increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT00211796	PHASE4	COMPLETED	Divalproex Sodium ER in Adult Autism
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT00409747	PHASE4	COMPLETED	Minocycline to Treat Childhood Regressive Autism
NCT00576732	PHASE4	COMPLETED	A Study of the Effectiveness and Safety of Two Doses of Risperidone in the Treatment of Children and Adolescents With Autistic Disorder
NCT00844753	PHASE4	COMPLETED	Atomoxetine, Placebo and Parent Management Training in Autism
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01098383	PHASE4	UNKNOWN	Treatment With Acetyl-Choline Esterase Inhibitors in Children With 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
NCT02069977	PHASE4	UNKNOWN	Study to Evaluate the Efficacy and Safety of Aripiprazole
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02199925	PHASE4	UNKNOWN	An Open-Label Study to Evaluate the Efficacy of High-Dose Gammaplex in Children on the Autism Spectrum
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02255565	PHASE4	COMPLETED	Dose Response Effects of Quillivant XR in Children With ADHD and Autism: A Pilot Study
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
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
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT00036231	PHASE3	TERMINATED	Synthetic Human Secretin in Children With Autism and Gastrointestinal Dysfunction