# NM_001282531.3(ADNP):c.2189del (p.Arg730fs)

https://sugi.bio/variant/adnp-p-arg730fs

## Summary

**ADNP p.Arg730fs (c.2189del)** is classified **Pathogenic** in ADNP (ClinVar, Single submitter, 2 submitters; last evaluated 2024-10-09). No gnomAD frequency available for this variant; Associated with ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2489790262 · 2 submitters · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the ADNP gene that is reported as disease-causing, but on limited review, submitted by 2 submitters, and is linked to ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Clinical trials | 2 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0012931/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ADNP](https://sugi.bio/atlas/gene/ADNP/) |
| Protein change (HGVS p.) | p.Arg730fs |
| Coding change (HGVS c.) | c.2189del |
| MANE Select transcript | [NM_001282531](https://www.ncbi.nlm.nih.gov/nuccore/NM_001282531) |
| dbSNP | [rs2489790262](https://www.ncbi.nlm.nih.gov/snp/rs2489790262/) |
| Variant type | Deletion |
| Location | chr20:50892525-50892525 (GRCh38) |
| ClinVar | [VCV3033209](https://www.ncbi.nlm.nih.gov/clinvar/variation/3033209/) |

**All HGVS expressions:** `NC_000020.10:g.49509062del`, `NC_000020.11:g.50892525del`, `NG_034200.1:g.43466del`, `NG_034200.2:g.43912del`, `NM_001282531.3:c.2189del`, `NM_001282532.2:c.2189del`, `NM_001347511.2:c.2189del`, `NM_015339.5:c.2189del`, `NM_181442.4:c.2189del`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -9.128, GERP -3.77 — fast-evolving / accelerated position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene (constraint LOEUF 0.106, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (6 of 6)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**ADNP** population constraint: LOEUF 0.106, pLI 1, missense-Z 2.5832; ClinGen dosage — haploinsufficiency 3, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 57.07, 6% of residues very-high.

## What this gene does {#gene-function}

*Describes the biological roles of ADNP (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*


### Pathways affected {#pathways}

ADNP participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [ChAHP complex assembly](https://reactome.org/content/detail/R-HSA-9940465) | electronic |

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-10-09.

**Submitter consensus:** unanimous (2/2 Pathogenic).

**Submission history:** 2 submissions (2023–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Pathogenic | no assertion criteria provided | clinical testing | 2023-12-12 |
| Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Pathogenic | criteria provided, single submitter | clinical testing | 2024-10-09 |

## Associated conditions {#conditions}

[ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder](https://sugi.bio/atlas/disease/adnp-related-multiple-congenital-anomalies-intellectual-disability-autism-spectrum-disorder/).

**Reported phenotype names (ClinVar):** ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder, ADNP-related disorder, ADNP-related condition, Helsmoortel-Van der Aa Syndrome, ADNP-Related Helsmoortel-Van der Aa Syndrome.

## Same-residue context {#hotspot}

Residue **730** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [ADNP p.Arg730Ter](/variant/adnp-p-arg730ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ADNP variant pages (same residue, condition, or type): [ADNP p.Arg730Ter](/variant/adnp-p-arg730ter), [ADNP p.Arg730Gln](/variant/adnp-p-arg730gln), [ADNP p.Leu831fs](/variant/adnp-p-leu831fs), [ADNP p.Lys773fs](/variant/adnp-p-lys773fs), [ADNP p.Lys829fs](/variant/adnp-p-lys829fs), [ADNP p.Ser955fs](/variant/adnp-p-ser955fs), [ADNP p.Thr718_Tyr719insTer](/variant/adnp-p-thr718-tyr719inster), [ADNP p.Val180fs](/variant/adnp-p-val180fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 3033209). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*