# NM_152424.4(AMER1):c.1441del (p.Asp481fs)

https://sugi.bio/variant/amer1-p-asp481fs

## Summary

**AMER1 p.Asp481fs (c.1441del)** is classified **Pathogenic** in AMER1 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-07-16). No gnomAD frequency available for this variant.

**At a glance:** Pathogenic · review: Single submitter · rsID rs1930253284 · 1 submitter · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the AMER1 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter.

*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 | [AMER1](https://sugi.bio/atlas/gene/AMER1/) |
| Protein change (HGVS p.) | p.Asp481fs |
| Coding change (HGVS c.) | c.1441del |
| MANE Select transcript | [NM_152424](https://www.ncbi.nlm.nih.gov/nuccore/NM_152424) |
| dbSNP | [rs1930253284](https://www.ncbi.nlm.nih.gov/snp/rs1930253284/) |
| Variant type | Deletion |
| Location | chrX:64191846-64191846 (GRCh38) |
| ClinVar | [VCV935942](https://www.ncbi.nlm.nih.gov/clinvar/variation/935942/) |

**All HGVS expressions:** `LRG_1259:g.18899del`, `LRG_1259t1:c.1441del`, `NC_000023.10:g.63411727del`, `NC_000023.11:g.64191847del`, `NG_021345.1:g.18899del`, `NM_152424.4:c.1441del`

## 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 6.094, GERP 1.85, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (2 of 2)** — 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}


Curated gene–disease validity (ClinGen):

- **osteopathia striata with cranial sclerosis** — Definitive (XL)

## Protein context {#protein}

Residue **481** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 48.88, 8% of residues very-high.

**3 experimental structure(s)** (PDB): [4YJE](https://www.rcsb.org/structure/4YJE), [4YJL](https://www.rcsb.org/structure/4YJL), [4YK6](https://www.rcsb.org/structure/4YK6).

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

*Describes the biological roles of AMER1 (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.*

**How this variant is thought to act:** AMER1's established molecular role includes phosphatidylinositol-4,5-bisphosphate binding. p.Asp481fs falls in the disordered region. In Reactome, AMER1 is annotated in disease pathway(s) including **APC truncation mutants have impaired AXIN binding**, **AXIN missense mutants destabilize the destruction complex**.

**Disease mechanism (Reactome):** AMER1 loss or alteration is curated in [APC truncation mutants have impaired AXIN binding](https://reactome.org/content/detail/R-HSA-5467337), [AXIN missense mutants destabilize the destruction complex](https://reactome.org/content/detail/R-HSA-5467340), [CTNNB1 S33 mutants aren't phosphorylated](https://reactome.org/content/detail/R-HSA-5358747).

### Pathways affected {#pathways}

AMER1 participates in **13 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [APC truncation mutants have impaired AXIN binding](https://reactome.org/content/detail/R-HSA-5467337) | curated |
| ⚕ [AXIN missense mutants destabilize the destruction complex](https://reactome.org/content/detail/R-HSA-5467340) | curated |
| ⚕ [CTNNB1 S33 mutants aren't phosphorylated](https://reactome.org/content/detail/R-HSA-5358747) | curated |
| ⚕ [CTNNB1 S37 mutants aren't phosphorylated](https://reactome.org/content/detail/R-HSA-5358749) | curated |
| ⚕ [CTNNB1 S45 mutants aren't phosphorylated](https://reactome.org/content/detail/R-HSA-5358751) | curated |
| ⚕ [CTNNB1 T41 mutants aren't phosphorylated](https://reactome.org/content/detail/R-HSA-5358752) | curated |
| ⚕ [Signaling by GSK3beta mutants](https://reactome.org/content/detail/R-HSA-5339716) | curated |
| ⚕ [Truncations of AMER1 destabilize the destruction complex](https://reactome.org/content/detail/R-HSA-5467348) | curated |
| [Beta-catenin phosphorylation cascade](https://reactome.org/content/detail/R-HSA-196299) | curated |
| [Degradation of beta-catenin by the destruction complex](https://reactome.org/content/detail/R-HSA-195253) | curated |
| [KEAP1-NFE2L2 pathway](https://reactome.org/content/detail/R-HSA-9755511) | curated |
| [Neddylation](https://reactome.org/content/detail/R-HSA-8951664) | curated |
| [Disassembly of the destruction complex and recruitment of AXIN to the membrane](https://reactome.org/content/detail/R-HSA-4641262) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** phosphatidylinositol-4,5-bisphosphate binding, beta-catenin binding, beta-catenin destruction complex binding.

**Biological process:** positive regulation of protein ubiquitination, positive regulation of protein catabolic process, regulation of canonical Wnt signaling pathway, negative regulation of canonical Wnt signaling pathway, positive regulation of canonical Wnt signaling pathway.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2019-07-16.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2019-07-16 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related AMER1 variant pages (same residue, condition, or type): [AMER1 p.Asp481His](/variant/amer1-p-asp481his), [AMER1 p.Arg497fs](/variant/amer1-p-arg497fs), [AMER1 p.Gln232fs](/variant/amer1-p-gln232fs), [AMER1 p.Leu406fs](/variant/amer1-p-leu406fs), [AMER1 p.Lys292fs](/variant/amer1-p-lys292fs), [AMER1 p.Asp315fs](/variant/amer1-p-asp315fs), [AMER1 p.Cys125fs](/variant/amer1-p-cys125fs), [AMER1 p.Cys216fs](/variant/amer1-p-cys216fs).

### 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 935942). 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.*