WAC

Chr 10AD

WW domain containing adaptor with coiled-coil

ENSG00000095787UniProt: Q9BTA9

Acts as a linker between gene transcription and histone H2B monoubiquitination at 'Lys-120' (H2BK120ub1) (PubMed:21329877). Interacts with the RNA polymerase II transcriptional machinery via its WW domain and with RNF20-RNF40 via its coiled coil region, thereby linking and regulating H2BK120ub1 and gene transcription (PubMed:21329877). Regulates the cell-cycle checkpoint activation in response to DNA damage (PubMed:21329877). Positive regulator of amino acid starvation-induced autophagy (PubMed:22354037). Also acts as a negative regulator of basal autophagy (PubMed:26812014). Positively regulates MTOR activity by promoting, in an energy-dependent manner, the assembly of the TTT complex composed of TELO2, TTI1 and TTI2 and the RUVBL complex composed of RUVBL1 and RUVBL2 into the TTT-RUVBL complex. This leads to the dimerization of the mTORC1 complex and its subsequent activation (PubMed:26812014). May negatively regulate the ubiquitin proteasome pathway (PubMed:21329877)

Primary Disease Associations & Inheritance

Desanto-Shinawi syndromeMIM #616708
AD
308
ClinVar variants
99
Pathogenic / LP
1.00
pLI score· haploinsufficient
2
Active trials
Clinical Summary— WAC
🧬
Gene-Disease Validity (ClinGen)
DeSanto-Shinawi 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· 116 VUS of 308 total submissions
💊
Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available
Some data sources returned errors (1)

ncbi: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esummary.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
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.
0.08LOEUF
pLI 1.000
Z-score 5.53
OE 0.00 (0.00–0.08)
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.
1.51Z-score
OE missense 0.77 (0.69–0.85)
262 obs / 340.5 exp
Tolerant

Mild missense constraint

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.0.00 (0.00–0.08)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.77 (0.69–0.85)
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.1.05
0≤1.21.6
LoF obs/exp: 0 / 35.6Missense obs/exp: 262 / 340.5Syn Z: -0.42

ClinVar Variant Classifications

308 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic79
Likely Pathogenic20
VUS116
Likely Benign61
Benign25
Conflicting7
79
Pathogenic
20
Likely Pathogenic
116
VUS
61
Likely Benign
25
Benign
7
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
46
0
33
0
79
Likely Pathogenic
14
0
6
0
20
VUS
2
100
12
2
116
Likely Benign
0
19
30
12
61
Benign
0
5
17
3
25
Conflicting
—7
Total621249817308

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

View in ClinVar →

Protein Context — Lollipop Plot

WAC · protein map & ClinVar variants

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

Gene2Phenotype Curations

WAC-related Desanto-Shinawi syndrome

definitive
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

Desanto-Shinawi syndrome

MIM #616708

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — WAC
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
De novo mutations in moderate or severe intellectual disability.
Hamdan FF et al.·PLoS Genet
2014
Tocilizumab for the management of immune mediated adverse events secondary to PD-1 blockade.
Stroud CR et al.·J Oncol Pharm Pract
2019
Phenotypic and Brain Imaging Findings Associated With a 10p Proximal Deletion Including the WAC Gene: Case Report and Literature Review.
Bolat H et al.·Cogn Behav Neurol
2022Review
A survey of colonoscopists with and without in-depth knowledge of water-aided colonoscopy.
Leung FW et al.·J Gastroenterol Hepatol
2022Meta-analysis
Nuclear Condensates of WW Domain-Containing Adaptor With Coiled-Coil Regulate Mitophagy via Alternative Splicing.
Wang J et al.·Adv Sci (Weinh)
2025
LncRNA WAC-AS1 expression in human tumors correlates with immune infiltration and affects prognosis.
Wang Y et al.·Hereditas
2023
Clinical and molecular characterization of five new individuals with WAC-related intellectual disability: Evidence of pathogenicity for a novel splicing variant.
Morales JA et al.·Am J Med Genet A
2022
Self-limited focal epilepsy and childhood apraxia of speech with WAC pathogenic variants.
Alawadhi A et al.·Eur J Paediatr Neurol
2021
The DESSH Clinic: A New Multidisciplinary Clinic to Address the Complex Needs of Individuals with a Rare Genetic Disorder.
Reynolds M et al.·Mo Med
2024
Comprehensive Analysis of RNA-Binding Protein-Related lncRNA in Breast Invasive Carcinoma.
Zhou J et al.·Front Biosci (Landmark Ed)
2023
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Structural insights into the Bre1-Lge1 and RNF20/RNF40-WAC interactions critical for H2B ubiquitination.
Shi M et al.·Nucleic Acids Res
2026🔓 Open Access
Characterization of WAC interactions with R2TP and TTT chaperone complexes linking glucose and glutamine availability to mTORC1 activity.
Cabezudo S et al.·FEBS Open Bio
2025🔓 Open Access
Inhibition of WAC alleviates the chondrocyte proinflammatory secretory phenotype and cartilage degradation via H2BK120ub1 and H3K27me3 coregulation.
Xu P et al.·Acta Pharm Sin B
2025🔓 Open Access
Comparative Studies of GAC Metric Tools AGREE, Analytical Eco-Scale, BAGI and WAC RGB Model to Determine Atorvastatin in Pharmaceuticals.
Haque SM.·Crit Rev Anal Chem
2025Functional
The WAC-downWAC domain in the yeast ISW2 nucleosome remodeling complex forms a structural module essential for ISW2 function but not cell viability.
Singh AK et al.·Epigenetics Chromatin
2025🔓 Open AccessFunctional
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
WACDeSanto-Shinawi SyndromeDESSH

Further Delineation of the De Santo Shinawi Syndrome Phenotype Using a Series of Individuals Carrying a Pathogenic Variant of the WAC Gene

RECRUITING
NCT06807723University Hospital, Clermont-FerrandStarted 2024-11-07

External Resources

Links to major genomics databases and tools