# NM_004068.4(AP2M1):c.783C>T (p.Arg261=)

https://sugi.bio/variant/ap2m1-p-arg261

## Summary

**AP2M1 p.Arg261= (c.783C>T)** is classified **Likely benign** in AP2M1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-27). Ultra-rare (popmax 0.0373%, afr).

**At a glance:** Likely benign · review: Single submitter · rsID rs144760576 · 1 submitter · ultra-rare (popmax 0.0373%, afr)

## For patients & families {#patients}

This is a change in the AP2M1 gene that is classified as likely benign — not considered disease-causing, 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.Arg261= |
| Coding change (HGVS c.) | c.783C>T |
| MANE Select transcript | [NM_004068](https://www.ncbi.nlm.nih.gov/nuccore/NM_004068) |
| dbSNP | [rs144760576](https://www.ncbi.nlm.nih.gov/snp/rs144760576/) |
| Variant type | single nucleotide variant |
| Location | chr3:184181771-184181771 (GRCh38) |
| ClinVar | [VCV1561588](https://www.ncbi.nlm.nih.gov/clinvar/variation/1561588/) |

**All HGVS expressions:** `NC_000003.11:g.183899559C>T`, `NC_000003.12:g.184181771C>T`, `NG_054899.1:g.697C>T`, `NM_001025205.2:c.777C>T`, `NM_001311198.2:c.858C>T`, `NM_004068.4:c.783C>T`

## 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 -0.083, GERP -1.55, phastCons 0.368 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 10.17**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0373%** (afr) · FAF95 0.0265% · FAF99 0.0229% · 28/75,048 in the highest group · 35/1,614,144 alleles overall — ultra-rare (popmax 0.0373%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0373% | 2,680 |
| Remaining individuals (not grpmax-eligible) | 0.008% | 12,501 |
| Admixed American | 0.00167% | 60,028 |
| Finnish (not grpmax-eligible) | 0.00156% | 64,034 |

*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 **261** lies in the mhd domain.

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.Arg261= 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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-06-27.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-06-27 |

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

## Similar variants {#similar}

Related AP2M1 variant pages (same residue, condition, or type): [AP2M1 p.Arg261Cys](/variant/ap2m1-p-arg261cys), [AP2M1 p.Arg170Trp](/variant/ap2m1-p-arg170trp), [AP2M1 p.Ala28Thr](/variant/ap2m1-p-ala28thr), [AP2M1 p.Arg169His](/variant/ap2m1-p-arg169his), [AP2M1 p.Arg199Gln](/variant/ap2m1-p-arg199gln), [AP2M1 p.Arg40Trp](/variant/ap2m1-p-arg40trp), [AP2M1 p.Arg44His](/variant/ap2m1-p-arg44his), [AP2M1 p.Cys246Arg](/variant/ap2m1-p-cys246arg).

### 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 1561588). 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.*