ADNP

Chr 20

activity dependent neuroprotector homeobox

NCBI Gene: 23394ENSG00000101126UniProt: Q9H2P0

May be involved in transcriptional regulation. May mediate some of the neuroprotective peptide VIP-associated effects involving normal growth and cancer proliferation. Positively modulates WNT-beta-catenin/CTNN1B signaling, acting by regulating phosphorylation of, and thereby stabilizing, CTNNB1. May be required for neural induction and neuronal differentiation. May be involved in erythroid differentiation (By similarity)

Primary Disease Associations & Inheritance

UniProtHelsmoortel-van der Aa syndrome
196
ClinVar variants
24
Pathogenic / LP
1.00
pLI score· haploinsufficient
2
Active trials
Clinical Summary— ADNP
🧬
Gene-Disease Validity (ClinGen)
ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder · 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
24 Pathogenic / Likely Pathogenic· 109 VUS of 196 total submissions
💊
Clinical Trials
2 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
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.
0.12LOEUF
pLI 1.000
Z-score 5.61
OE 0.03 (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.
2.07Z-score
OE missense 0.76 (0.70–0.82)
439 obs / 579.4 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.0.03 (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.0.76 (0.70–0.82)
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.1.34
0≤1.21.6
LoF obs/exp: 1 / 38.7Missense obs/exp: 439 / 579.4Syn Z: -3.92

ClinVar Variant Classifications

196 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic14
Likely Pathogenic10
VUS109
Likely Benign50
Benign2
Conflicting11
14
Pathogenic
10
Likely Pathogenic
109
VUS
50
Likely Benign
2
Benign
11
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
6
1
7
0
14
Likely Pathogenic
7
1
2
0
10
VUS
1
96
9
3
109
Likely Benign
0
17
5
28
50
Benign
0
0
0
2
2
Conflicting
—11
Total141152333196

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

View in ClinVar →

Protein Context — Lollipop Plot

ADNP · protein map & ClinVar variants

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

Gene2Phenotype Curations

ADNP-related neurodevelopmental disorder (Helsmoortel-Van der Aa Syndrome)

definitive
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 — ADNP
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP.
Van Dijck A et al.·Biol Psychiatry
2019
Activity-dependent neuroprotective protein (ADNP)-end-binding protein (EB) interactions regulate microtubule dynamics toward protection against tauopathy.
Ivashko-Pachima Y et al.·Prog Mol Biol Transl Sci
2021Review
Chromatin remodeler Activity-Dependent Neuroprotective Protein (ADNP) contributes to syndromic autism.
D'Incal CP et al.·Clin Epigenetics
2023Review
Clinical impact and in vitro characterization of ADNP variants in pediatric patients.
Ge C et al.·Mol Autism
2024Cohort
Blepharophimosis with intellectual disability and Helsmoortel-Van Der Aa Syndrome share episignature and phenotype.
Sarli C et al.·Am J Med Genet C Semin Med Genet
2024
Gastric Adenocarcinoma with Enteroblastic Differentiation.
Ferenczi Á et al.·Pathobiology
2025Review
Shared and divergent mental health characteristics of ADNP-, CHD8- and DYRK1A-related neurodevelopmental conditions.
Neuhaus E et al.·J Neurodev Disord
2024
ADNP is associated with immune infiltration and radiosensitivity in hepatocellular carcinoma for predicting the prognosis.
Wang X et al.·BMC Med Genomics
2023
ADNP is essential for sex-dependent hippocampal neurogenesis, through male unfolded protein response and female mitochondrial gene regulation.
Shapira G et al.·Mol Psychiatry
2025
Intranasal NAP (Davunetide): Neuroprotection and circadian rhythmicity.
Galushkin A et al.·Adv Drug Deliv Rev
2025Review
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
ADNPHelsmoortel-Van Der Aa SyndromeAutism Spectrum Disorder

ADNP Syndrome: The Seaver Autism Center for Research and Treatment is Characterizing ADNP-related Neurodevelopmental Disorders Using Genetic, Medical, and Neuropsychological Measures.

RECRUITING
NCT03718936Icahn School of Medicine at Mount SinaiStarted 2017-11-14

External Resources

Links to major genomics databases and tools