ADNP

Chr 20AD

activity dependent neuroprotector homeobox

Also known as: ADNP1, HVDAS, MRD28

NCBI Gene: 23394 ENSG00000101126 UniProt: Q9H2P0 OMIM: 611386

This gene encodes a transcription factor containing homeobox and zinc finger domains that is upregulated by vasoactive intestinal peptide and modulates p53 activity to promote cell viability. Mutations cause Helsmoortel-van der Aa syndrome through an autosomal dominant inheritance pattern, predominantly through loss-of-function mechanisms. The gene shows extreme intolerance to loss-of-function variants, consistent with haploinsufficiency as the primary pathogenic mechanism.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

LOFmechanismADLOEUF 0.121 OMIM phenotype

Clinical Summary— ADNP

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Gene-Disease Validity (ClinGen)

ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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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.

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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint

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

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

LoF OE0.03 (0.01–0.12)

0≤0.351.4

Missense OE0.76 (0.70–0.82)

0≤0.61.4

Synonymous OE1.34

0≤1.21.6

LoF obs/exp: 1 / 38.7Missense obs/exp: 439 / 579.4Syn Z: -3.92

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveADNP-related neurodevelopmental disorder (Helsmoortel-Van der Aa Syndrome)LOFAD

0.19100th %ile

GOF

0.1799th %ile

LOF

0.85top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · LOEUF 0.12

DN1 literature citation

Literature Evidence

DNHelsmoortel et al. (2014) noted that mutations in other SWI/SNF components of the BAF complex, such as SMARCB1 (601607) and ARID1B (614556), have been identified in patients with intellectual disability, and hypothesized that the ADNP mutations cause a dominant-negative effect on the recruitment of PMID:24531329

LOFHere, we extended the ADNP syndrome phenotype describing skin abnormalities in both a patient with ADNP syndrome and an Adnp haploinsufficient mice.PMID:30679581

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

0 submitted variants in ClinVar

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.

3D Protein StructureAlphaFold

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

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

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

Clinical Literature

Open Research Assistant →

Landmark / reviewRecent case evidence

Full-Text Mentions

NLP-detected gene mentions in article bodies · via PubTator3

PubTator3