# NM_004069.6(AP2S1):c.182G>A (p.Arg61His)

https://sugi.bio/variant/ap2s1-p-arg61his

## Summary

**AP2S1 p.Arg61His (c.182G>A)** is classified **Uncertain significance** in AP2S1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-22). AlphaMissense: likely pathogenic (0.9547); Very rare (popmax 8.47e-05%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs754997253 · 1 submitter · AlphaMissense likely pathogenic · very rare (popmax 8.47e-05%, nfe)

## For patients & families {#patients}

This is a change in the AP2S1 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 | [AP2S1](https://sugi.bio/atlas/gene/AP2S1/) |
| Protein change (HGVS p.) | p.Arg61His |
| Coding change (HGVS c.) | c.182G>A |
| MANE Select transcript | [NM_004069](https://www.ncbi.nlm.nih.gov/nuccore/NM_004069) |
| dbSNP | [rs754997253](https://www.ncbi.nlm.nih.gov/snp/rs754997253/) |
| Variant type | single nucleotide variant |
| Location | chr19:46839550-46839550 (GRCh38) |
| ClinVar | [VCV2502631](https://www.ncbi.nlm.nih.gov/clinvar/variation/2502631/) |

**All HGVS expressions:** `NC_000019.10:g.46839550C>T`, `NC_000019.9:g.47342807C>T`, `NG_033136.1:g.16397G>A`, `NM_001301076.3:c.230G>A`, `NM_001301078.3:c.224G>A`, `NM_001301081.3:c.188G>A`, `NM_004069.6:c.182G>A`, `NM_021575.5:c.154-751G>A`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.9547)
- REVEL 0.447 (indeterminate)
- SaProt LLR -13.142 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL makes no call
- Conservation: phyloP 7.432, GERP 1.85, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 32.0**. 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.*
- Regional missense constraint: **o/e 0.32** across the covering region of the MANE Select transcript (46,838,450–46,850,766), spanning 12,316 bp — the region is depleted of missense variation. Chi-square p 2.2e-20. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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 **8.47e-05%** (nfe) · 1/1,180,018 in the highest group · 1/1,461,870 alleles overall — very rare (popmax 8.47e-05%, nfe).

*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}

**AP2S1** population constraint: LOEUF 0.478, pLI 0.98109, missense-Z 3.5198. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **61** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 97.03, 97% of residues very-high.

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

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

*Describes the biological roles of AP2S1 (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:** AP2S1 participates in disease-associated pathways. In Reactome, AP2S1 is annotated in disease pathway(s) including **Dengue Virus Attachment and Entry**, **Nef Mediated CD4 Down-regulation**.

**Disease mechanism (Reactome):** AP2S1 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}

AP2S1 participates in **15 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 |
| ⚕ [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 |
| [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}

**Biological process:** synaptic vesicle endocytosis.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-11-22.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-11-22 |

**Reported phenotype names (ClinVar):** not provided, none provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM.

## Similar variants {#similar}

Related AP2S1 variant pages (same residue, condition, or type): [AP2S1 p.Arg61Cys](/variant/ap2s1-p-arg61cys), [AP2S1 p.Arg15Cys](/variant/ap2s1-p-arg15cys), [AP2S1 p.Arg15His](/variant/ap2s1-p-arg15his), [AP2S1 p.Arg15Leu](/variant/ap2s1-p-arg15leu), [AP2S1 c.153+5C>T](/variant/ap2s1-c-153-plus-5c-t), [AP2S1 p.Arg60His](/variant/ap2s1-p-arg60his), [AP2S1 p.Gln22His](/variant/ap2s1-p-gln22his), [AP2S1 p.Ile84Val](/variant/ap2s1-p-ile84val).

### 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 2502631). 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.*