# NM_001282531.3(ADNP):c.1184dup (p.Ser396fs)

https://sugi.bio/variant/adnp-p-ser396fs

## Summary

**ADNP p.Ser396fs (c.1184dup)** is classified **Pathogenic** in ADNP (ClinVar, No assertion criteria, 1 submitter; last evaluated 2017-12-01). No gnomAD frequency available for this variant; Associated with intellectual disability.

**At a glance:** Pathogenic · review: No assertion criteria · rsID rs1981038382 · 1 submitter · 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 1 submitter, and is linked to intellectual disability.

*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 | 204 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | ADNP is a diagnostic-grade gene on 6 Genomics England panels |

**Support & next steps:** [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.Ser396fs |
| Coding change (HGVS c.) | c.1184dup |
| MANE Select transcript | [NM_001282531](https://www.ncbi.nlm.nih.gov/nuccore/NM_001282531) |
| dbSNP | [rs1981038382](https://www.ncbi.nlm.nih.gov/snp/rs1981038382/) |
| Variant type | Duplication |
| Location | chr20:50893529-50893530 (GRCh38) |
| ClinVar | [VCV973125](https://www.ncbi.nlm.nih.gov/clinvar/variation/973125/) |

**All HGVS expressions:** `NC_000020.10:g.49510067dup`, `NC_000020.11:g.50893530dup`, `NG_034200.1:g.42461dup`, `NM_001282531.3:c.1184dup`, `NM_001282532.2:c.1184dup`, `NM_001347511.2:c.1184dup`, `NM_015339.5:c.1184dup`, `NM_181442.4:c.1184dup`

## 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 1.121, GERP -2.44, phastCons 0.999 — weakly conserved 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 duplication 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}

Residue **396** lies in the 'disordered' region.

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 No assertion criteria *(no assertion criteria provided)*, last evaluated 2017-12-01.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Diagnostic Laboratory, Strasbourg University Hospital | Pathogenic | no assertion criteria provided | clinical testing | 2017-12-01 |

## Associated conditions {#conditions}

[intellectual disability](https://sugi.bio/atlas/disease/intellectual-disability/).

**Reported phenotype names (ClinVar):** Intellectual disability, intellectual disabilities, Intellectual developmental disorder, Intellectual functioning disability.

## Similar variants {#similar}

Related ADNP variant pages (same residue, condition, or type): [ADNP p.Arg216Ter](/variant/adnp-p-arg216ter), [ADNP p.Leu831fs](/variant/adnp-p-leu831fs), [ADNP p.Ile1069Val](/variant/adnp-p-ile1069val), [ADNP c.-89-3923_201+2793inv](/variant/adnp-c-minus-89-minus-3923-201-plus-2793inv), [ADNP p.Gln414fs](/variant/adnp-p-gln414fs), [ADNP p.Gln414Ter](/variant/adnp-p-gln414ter), [ADNP p.Leu23fs](/variant/adnp-p-leu23fs), [ADNP p.Arg296Trp](/variant/adnp-p-arg296trp).

### 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 973125). 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.*