# NM_001272071.2(AP1S2):c.178dup (p.Arg60fs)

https://sugi.bio/variant/ap1s2-p-arg60fs

## Summary

**AP1S2 p.Arg60fs (c.178dup)** is classified **Pathogenic** in AP1S2 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-07-01). No gnomAD frequency available for this variant.

**At a glance:** Pathogenic · review: Single submitter · rsID rs1934205000 · 1 submitter · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the AP1S2 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 | [AP1S2](https://sugi.bio/atlas/gene/AP1S2/) |
| Protein change (HGVS p.) | p.Arg60fs |
| Coding change (HGVS c.) | c.178dup |
| MANE Select transcript | [NM_001272071](https://www.ncbi.nlm.nih.gov/nuccore/NM_001272071) |
| dbSNP | [rs1934205000](https://www.ncbi.nlm.nih.gov/snp/rs1934205000/) |
| Variant type | Duplication |
| Location | chrX:15852346-15852347 (GRCh38) |
| ClinVar | [VCV1012855](https://www.ncbi.nlm.nih.gov/clinvar/variation/1012855/) |

**All HGVS expressions:** `NC_000023.10:g.15870473dup`, `NC_000023.11:g.15852350dup`, `NG_009274.2:g.7631dup`, `NM_001272071.2:c.178dup`, `NM_001368994.1:c.178dup`, `NM_001369007.1:c.178dup`, `NM_001369008.1:c.178dup`, `NM_003916.5:c.178dup`, `NR_160932.1:n.304dup`, `NR_160933.1:n.304dup`

## 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 7.702, GERP 1.88, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene, supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 6**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication 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}

**AP1S2** population constraint: 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):

- **X-linked syndromic complex neurodevelopmental disorder** — Definitive (XL)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 94.36, 91% of residues very-high.

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

*Describes the biological roles of AP1S2 (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:** AP1S2 participates in disease-associated pathways. In Reactome, AP1S2 is annotated in disease pathway(s) including **Nef mediated downregulation of MHC class I complex cell surface expression**.

**Disease mechanism (Reactome):** AP1S2 loss or alteration is curated in [Nef mediated downregulation of MHC class I complex cell surface expression](https://reactome.org/content/detail/R-HSA-164940).

### Pathways affected {#pathways}

AP1S2 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Nef mediated downregulation of MHC class I complex cell surface expression](https://reactome.org/content/detail/R-HSA-164940) | curated |
| [Golgi Associated Vesicle Biogenesis](https://reactome.org/content/detail/R-HSA-432722) | curated |
| [Lysosome Vesicle Biogenesis](https://reactome.org/content/detail/R-HSA-432720) | curated |
| [MHC class II antigen presentation](https://reactome.org/content/detail/R-HSA-2132295) | curated |

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2020-07-01.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| CeGaT Center for Human Genetics Tuebingen | Pathogenic | criteria provided, single submitter | clinical testing | 2020-07-01 |

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

## Similar variants {#similar}

Related AP1S2 variant pages (same residue, condition, or type): [AP1S2 c.289-10dup](/variant/ap1s2-c-289-minus-10dup).

### 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 2026-07-14); 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 1012855). 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.*