SHANK3

Chr 22

SH3 and multiple ankyrin repeat domains 3

Also known as: DEL22q13.3, PROSAP2, PSAP2, SCZD15, SPANK-2

NCBI Gene: 85358ENSG00000251322UniProt: Q9BYB0

This gene is a member of the Shank gene family. Shank proteins are multidomain scaffold proteins of the postsynaptic density that connect neurotransmitter receptors, ion channels, and other membrane proteins to the actin cytoskeleton and G-protein-coupled signaling pathways. Shank proteins also play a role in synapse formation and dendritic spine maturation. Mutations in this gene are a cause of autism spectrum disorder (ASD), which is characterized by impairments in social interaction and communication, and restricted behavioral patterns and interests. Mutations in this gene also cause schizophrenia type 15, and are a major causative factor in the neurological symptoms of 22q13.3 deletion syndrome, which is also known as Phelan-McDermid syndrome. Additional isoforms have been described for this gene but they have not yet been experimentally verified. [provided by RefSeq, Mar 2012]

Primary Disease Associations & Inheritance

UniProtPhelan-McDermid syndrome
UniProtSchizophrenia 15
676
ClinVar variants
99
Pathogenic / LP
1.00
pLI score· haploinsufficient
4
Active trials
Clinical Summary— SHANK3
🧬
Gene-Disease Validity (ClinGen)
Phelan-McDermid syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
99 Pathogenic / Likely Pathogenic· 355 VUS of 676 total submissions
💊
Clinical Trials
4 active or recruiting trials — potential therapeutic options may be available
Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.12LOEUF
pLI 1.000
Z-score 6.36
OE 0.04 (0.01–0.12)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
3.74Z-score
OE missense 0.65 (0.60–0.69)
571 obs / 884.2 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.04 (0.01–0.12)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.65 (0.60–0.69)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.21
0≤1.21.6
LoF obs/exp: 2 / 51.0Missense obs/exp: 571 / 884.2Syn Z: -3.40

ClinVar Variant Classifications

676 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic78
Likely Pathogenic21
VUS355
Likely Benign140
Benign73
Conflicting9
78
Pathogenic
21
Likely Pathogenic
355
VUS
140
Likely Benign
73
Benign
9
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
32
0
46
0
78
Likely Pathogenic
17
1
3
0
21
VUS
6
230
110
9
355
Likely Benign
0
24
32
84
140
Benign
1
2
67
3
73
Conflicting
—9
Total5625725896676

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

SHANK3 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

SHANK3-related Phelan-Mcdermid syndrome

strong
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

📖
GeneReview available — SHANK3
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Updated consensus guidelines on the management of Phelan-McDermid syndrome.
Srivastava S et al.·Am J Med Genet A
2023Review
Autism spectrum disorder: neuropathology and animal models.
Varghese M et al.·Acta Neuropathol
2017Review
Clinical and genetic characteristics and prenatal diagnosis of patients presented GDD/ID with rare monogenic causes.
Lin L et al.·Orphanet J Rare Dis
2020Cohort
New Candidates for Autism/Intellectual Disability Identified by Whole-Exome Sequencing.
Bruno LP et al.·Int J Mol Sci
2021Clinical trial
Shank3 mutation impairs glutamate signaling and myelination in ASD mouse model and human iPSC-derived OPCs.
Fischer I et al.·Sci Adv
2024Functional
De Novo Variants in CNOT1, a Central Component of the CCR4-NOT Complex Involved in Gene Expression and RNA and Protein Stability, Cause Neurodevelopmental Delay.
Vissers LELM et al.·Am J Hum Genet
2020
Axin2 coupled excessive Wnt-glycolysis signaling mediates social defect in autism spectrum disorders.
Wang M et al.·EMBO Mol Med
2023
Evidence for common mechanisms of pathology between SHANK3 and other genes of Phelan-McDermid syndrome.
Mitz AR et al.·Clin Genet
2024Review
SHANK3 variant as a cause of nonsyndromal autism in an 11-year-old boy and a review of published literature.
Kanani F et al.·Clin Dysmorphol
2018Review
Restoring thalamocortical circuit dysfunction by correcting HCN channelopathy in Shank3 mutant mice.
Guo B et al.·Cell Rep Med
2024
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Abnormal Neuronal Excitability and Reduced Parvalbumin Expression in Shank3-Deficient Parvalbumin Neurons of the Thalamic Reticular Nucleus.
Lai Y et al.·J Neurosci
2026
Nitric Oxide-Mediated S-Nitrosylation of TSC2 Drives mTOR dysregulation across Shank3 and Cntnap2 Models of Autism Spectrum Disorder.
Ojha SK et al.·Mol Psychiatry
2026Functional
Extracellular vesicles from stem cells rescue cellular phenotypes and behavioral deficits in SHANK3-associated ASD neuronal and mouse models.
Choudhary A et al.·Cell Death Dis
2026🔓 Open AccessFunctional
Chrysin Ameliorates Valproic Acid Induced Autism Spectrum Behavioral Phenotypes Through Corticohippocampal Histone Deacetylase and Translational Modulation of SHANK3 Expression in Juvenile Rats.
Adeniyi IA et al.·J Mol Neurosci
2026
Early-life sleep disruption in Shank3-deficient rats: A preclinical model for autism-related sleep mechanisms and interventions.
Qiu MH et al.·Transl Psychiatry
2026Functional
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
SHANK3 HaploinsufficiencyPhelan-McDermid Syndrome

JAG201 Gene Therapy Study in Children & Adults With SHANK3 Haploinsufficiency

RECRUITING
NCT06662188Phase PHASE1, PHASE2Jaguar Gene Therapy, LLCStarted 2024-01-07
JAG201JAG201
Genetic Disease

Multicenter Study of Patients With SHANK3 Mutations: Identification of Genes Modificators in Phelan-McDermid Syndrome (EUQ13)

NOT YET RECRUITING
NCT07119606Phase NAAssistance Publique - Hôpitaux de ParisStarted 2025-09-01
SHANK3 mutation
Autism DisorderASD

GENES AND AUTISM - IPSC

NOT YET RECRUITING
NCT07311213Phase NAInstitut National de la Santé Et de la Recherche Médicale, FranceStarted 2026-02-01
Blood Sample : isolation of peripheral blood mononuclear cells (PBMCs)
Phelan-McDermid SyndromeSHANK3 Haploinsufficiency

RB001 Gene Therapy Study in Children With SHANK3-related Phelan McDermid Syndrome (PMS)

RECRUITING
NCT07014020Phase NAPeking University First HospitalStarted 2025-06-16
RB001

External Resources

Links to major genomics databases and tools