SHANK2

Chr 11

SH3 and multiple ankyrin repeat domains 2

NCBI Gene: 22941ENSG00000162105UniProt: 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. May play a role in the structural and functional organization of the dendritic spine and synaptic junction

Primary Disease Associations & Inheritance

{Autism susceptibility 17}MIM #613436
UniProtAutism 17
508
ClinVar variants
57
Pathogenic / LP
0.00
pLI score
1
Active trials
Clinical Summary— SHANK2
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.33) despite low pLI — interpret in context.
📋
ClinVar Variants
57 Pathogenic / Likely Pathogenic· 235 VUS of 508 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
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.
0.46LOEUF
pLI 0.000
Z-score 5.51
OE 0.33 (0.24–0.46)
Moderately constrained

More LoF-intolerant than ~75% of genes

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.
2.32Z-score
OE missense 0.81 (0.76–0.85)
923 obs / 1144.3 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

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.0.33 (0.24–0.46)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.81 (0.76–0.85)
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.1.01
0≤1.21.6
LoF obs/exp: 26 / 78.8Missense obs/exp: 923 / 1144.3Syn Z: -0.22

ClinVar Variant Classifications

508 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic27
Likely Pathogenic30
VUS235
Likely Benign156
Benign16
Conflicting18
27
Pathogenic
30
Likely Pathogenic
235
VUS
156
Likely Benign
16
Benign
18
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
11
1
15
0
27
Likely Pathogenic
18
1
11
0
30
VUS
21
168
32
14
235
Likely Benign
0
51
15
90
156
Benign
0
5
3
8
16
Conflicting
—18
Total5022676112482

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

View in ClinVar →

Protein Context — Lollipop Plot

SHANK2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

SHANK2-related susceptibility to autism

strong
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

{Autism susceptibility 17}

MIM #613436

Molecular basis of disorder known

Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Phenotypic spectrum of SHANK2-related neurodevelopmental disorder.
Caumes R et al.·Eur J Med Genet
2020Review
Protein-truncating variants and deletions of SHANK2 are associated with autism spectrum disorder and other neurodevelopmental concerns.
Silver H et al.·J Neurodev Disord
2025
Identification of a Novel SHANK2 Pathogenic Variant in a Patient with a Neurodevelopmental Disorder.
Doddato G et al.·Genes (Basel)
2022Case report
Genetic Alterations in a Large Population of Italian Patients Affected by Neurodevelopmental Disorders.
Ranieri A et al.·Genes (Basel)
2024Cohort
Paracentric inversion disrupting the SHANK2 gene.
Huyghebaert J et al.·Eur J Med Genet
2025Case report
Autism patient-derived SHANK2B(Y29X) mutation affects the development of ALDH1A1 negative dopamine neuron.
Lai W et al.·Mol Psychiatry
2024
Genetic Analysis Implicates Dysregulation of SHANK2 in Renal Cell Carcinoma Progression.
Chang CF et al.·Int J Environ Res Public Health
2022
The emerging role of SHANK genes in neuropsychiatric disorders.
Guilmatre A et al.·Dev Neurobiol
2014Review
Structural deficits in key domains of Shank2 lead to alterations in postsynaptic nanoclusters and to a neurodevelopmental disorder in humans.
Hassani Nia F et al.·Mol Psychiatry
2024
Zinc deficiency and supplementation in autism spectrum disorder and Phelan-McDermid syndrome.
Alsufiani HM et al.·J Neurosci Res
2022Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
16P11.2 Deletion Syndrome16p11.2 Duplications1Q21.1 Deletion

Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight

RECRUITING
NCT01238250Simons SearchlightStarted 2010-10

External Resources

Links to major genomics databases and tools