# NM_004068.4(AP2M1):c.792del (p.Phe265fs)

https://sugi.bio/variant/ap2m1-p-phe265fs

## Summary

**AP2M1 p.Phe265fs (c.792del)** is classified **Uncertain significance** in AP2M1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-01). No gnomAD frequency available for this variant.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2473725328 · 1 submitter · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the AP2M1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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 | [AP2M1](https://sugi.bio/atlas/gene/AP2M1/) |
| Protein change (HGVS p.) | p.Phe265fs |
| Coding change (HGVS c.) | c.792del |
| MANE Select transcript | [NM_004068](https://www.ncbi.nlm.nih.gov/nuccore/NM_004068) |
| dbSNP | [rs2473725328](https://www.ncbi.nlm.nih.gov/snp/rs2473725328/) |
| Variant type | Deletion |
| Location | chr3:184181780-184181780 (GRCh38) |
| ClinVar | [VCV2853345](https://www.ncbi.nlm.nih.gov/clinvar/variation/2853345/) |

**All HGVS expressions:** `NC_000003.11:g.183899568del`, `NC_000003.12:g.184181780del`, `NG_054899.1:g.706del`, `NM_001025205.2:c.786del`, `NM_001311198.2:c.867del`, `NM_004068.4:c.792del`

## 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 9.949, GERP 0.703, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.182, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 8 of 12**, so the transcript is predicted to undergo NMD.
- 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}

**AP2M1** population constraint: LOEUF 0.182, pLI 1, missense-Z 6.3671. *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):

- **complex neurodevelopmental disorder** — Definitive (AD)

## Protein context {#protein}

Residue **265** lies in the mhd domain; a β-strand.

AlphaFold model confidence (whole protein): pLDDT 89.44, 72% of residues very-high.

**3 experimental structure(s)** (PDB): [1H6E](https://www.rcsb.org/structure/1H6E), [6BNT](https://www.rcsb.org/structure/6BNT), [6URI](https://www.rcsb.org/structure/6URI).

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

*Describes the biological roles of AP2M1 (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:** AP2M1's established molecular role includes signal sequence receptor activity. p.Phe265fs falls in the mhd domain. In Reactome, AP2M1 is annotated in disease pathway(s) including **Dengue Virus Attachment and Entry**, **Nef Mediated CD4 Down-regulation**.

**Disease mechanism (Reactome):** AP2M1 loss or alteration is curated in [Dengue Virus Attachment and Entry](https://reactome.org/content/detail/R-HSA-9918485), [Nef Mediated CD4 Down-regulation](https://reactome.org/content/detail/R-HSA-167590), [Nef Mediated CD8 Down-regulation](https://reactome.org/content/detail/R-HSA-182218).

### Pathways affected {#pathways}

AP2M1 participates in **18 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Dengue Virus Attachment and Entry](https://reactome.org/content/detail/R-HSA-9918485) | curated |
| ⚕ [Nef Mediated CD4 Down-regulation](https://reactome.org/content/detail/R-HSA-167590) | curated |
| ⚕ [Nef Mediated CD8 Down-regulation](https://reactome.org/content/detail/R-HSA-182218) | curated |
| ⚕ [Nef mediated downregulation of CD28 cell surface expression](https://reactome.org/content/detail/R-HSA-164939) | curated |
| ⚕ [Potential therapeutics for SARS](https://reactome.org/content/detail/R-HSA-9679191) | curated |
| [Cargo recognition for clathrin-mediated endocytosis](https://reactome.org/content/detail/R-HSA-8856825) | curated |
| [Clathrin-mediated endocytosis](https://reactome.org/content/detail/R-HSA-8856828) | curated |
| [EPH-ephrin mediated repulsion of cells](https://reactome.org/content/detail/R-HSA-3928665) | curated |
| [Formation of annular gap junctions](https://reactome.org/content/detail/R-HSA-196025) | curated |
| [Gap junction degradation](https://reactome.org/content/detail/R-HSA-190873) | curated |
| [LDL clearance](https://reactome.org/content/detail/R-HSA-8964038) | curated |
| [MHC class II antigen presentation](https://reactome.org/content/detail/R-HSA-2132295) | curated |
| [VLDLR internalisation and degradation](https://reactome.org/content/detail/R-HSA-8866427) | curated |
| [WNT5A-dependent internalization of FZD2, FZD5 and ROR2](https://reactome.org/content/detail/R-HSA-5140745) | curated |
| [WNT5A-dependent internalization of FZD4](https://reactome.org/content/detail/R-HSA-5099900) | curated |
| [Recycling pathway of L1](https://reactome.org/content/detail/R-HSA-437239) | electronic |
| [Retrograde neurotrophin signalling](https://reactome.org/content/detail/R-HSA-177504) | electronic |
| [Trafficking of GluR2-containing AMPA receptors](https://reactome.org/content/detail/R-HSA-416993) | other |

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

**Molecular function:** signal sequence receptor activity, transmembrane transporter binding.

**Biological process:** vesicle budding from membrane, receptor internalization, synaptic vesicle endocytosis, clathrin-dependent endocytosis, regulation of vesicle size, negative regulation of protein localization to plasma membrane.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-05-01.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-05-01 |

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

## Similar variants {#similar}

Related AP2M1 variant pages (same residue, condition, or type): [AP2M1 c.430-7del](/variant/ap2m1-c-430-minus-7del), [AP2M1 c.58_74+7del](/variant/ap2m1-c-58-74-plus-7del), [AP2M1 p.Asn9fs](/variant/ap2m1-p-asn9fs), [AP2M1 c.74+11_74+17del](/variant/ap2m1-c-74-plus-11-74-plus-17del), [AP2M1 c.963+18_963+20del](/variant/ap2m1-c-963-plus-18-963-plus-20del), [AP2M1 c.963+9_963+10del](/variant/ap2m1-c-963-plus-9-963-plus-10del), [AP2M1 c.*5del](/variant/ap2m1-c-star-5del).

### 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 2853345). 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.*