# NM_001282531.3(ADNP):c.2865_2868del (p.Ser955fs)

https://sugi.bio/variant/adnp-p-ser955fs

## Summary

**ADNP p.Ser955fs (c.2865_2868del)** is classified **Pathogenic/Likely pathogenic** in ADNP (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-11-14). No gnomAD frequency available for this variant; Associated with Inborn genetic diseases.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs1980777288 · 4 submitters · 2 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the ADNP gene that is considered likely disease-causing, submitted by 4 submitters, and is linked to Inborn genetic diseases.

*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.*

**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.Ser955fs |
| Coding change (HGVS c.) | c.2865_2868del |
| MANE Select transcript | [NM_001282531](https://www.ncbi.nlm.nih.gov/nuccore/NM_001282531) |
| dbSNP | [rs1980777288](https://www.ncbi.nlm.nih.gov/snp/rs1980777288/) |
| Variant type | Deletion |
| Location | chr20:50891846-50891849 (GRCh38) |
| ClinVar | [VCV984844](https://www.ncbi.nlm.nih.gov/clinvar/variation/984844/) |

**All HGVS expressions:** `NC_000020.10:g.49508385_49508388del`, `NC_000020.11:g.50891848_50891851del`, `NG_034200.1:g.44142_44145del`, `NM_001282531.2:c.2865_2868delTGAG`, `NM_001282531.3:c.2865_2868del`, `NM_001282532.2:c.2865_2868del`, `NM_001347511.2:c.2865_2868del`, `NM_015339.2:c.2865_2868del`, `NM_015339.2:c.2865_2868delTGAG`, `NM_015339.5:c.2865_2868del`, `NM_181442.4:c.2865_2868del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 4.052, GERP 1.89, phastCons 0.999 — highly conserved position (PP3-type support)
- 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}

Residue **955** lies in the 'disordered' region; a modified residue (phosphoserine).

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/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-11-14.

**Submitter consensus:** conflicting (3 Pathogenic, 1 Likely pathogenic).

**Submission history:** 4 submissions (2016–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2022-02-18 |
| Ambry Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2020-06-09 |
| GenomeConnect - Simons Searchlight | Pathogenic | no assertion criteria provided | provider interpretation | 2016-03-23 |
| Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Pathogenic | criteria provided, single submitter | clinical testing | 2024-11-14 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/), [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):** Inborn genetic diseases, ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder, not provided, ADNP-Related Helsmoortel-Van der Aa Syndrome, Helsmoortel-Van der Aa Syndrome, none provided.

## Similar variants {#similar}

Related ADNP variant pages (same residue, condition, or type): [ADNP p.Leu831fs](/variant/adnp-p-leu831fs), [ADNP p.Lys773fs](/variant/adnp-p-lys773fs), [ADNP p.Lys829fs](/variant/adnp-p-lys829fs), [ADNP p.Thr718_Tyr719insTer](/variant/adnp-p-thr718-tyr719inster), [ADNP p.Val180fs](/variant/adnp-p-val180fs), [ADNP p.Arg730fs](/variant/adnp-p-arg730fs), [ADNP p.Asn108fs](/variant/adnp-p-asn108fs), [ADNP p.Asn214fs](/variant/adnp-p-asn214fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 984844). 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.*