# NM_001253852.3(AP4B1):c.1655del (p.Pro552fs)

https://sugi.bio/variant/ap4b1-p-pro552fs

## Summary

**AP4B1 p.Pro552fs (c.1655del)** is classified **Likely pathogenic** in AP4B1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-10-01). No gnomAD frequency available for this variant; Associated with Spastic paraplegia.

**At a glance:** Likely pathogenic · review: No assertion criteria · rsID rs2100994885 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the AP4B1 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to Spastic paraplegia.

*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 | [AP4B1](https://sugi.bio/atlas/gene/AP4B1/) |
| Protein change (HGVS p.) | p.Pro552fs |
| Coding change (HGVS c.) | c.1655del |
| MANE Select transcript | [NM_001253852](https://www.ncbi.nlm.nih.gov/nuccore/NM_001253852) |
| dbSNP | [rs2100994885](https://www.ncbi.nlm.nih.gov/snp/rs2100994885/) |
| Variant type | Deletion |
| Location | chr1:113895894-113895894 (GRCh38) |
| ClinVar | [VCV1344780](https://www.ncbi.nlm.nih.gov/clinvar/variation/1344780/) |

**All HGVS expressions:** `NC_000001.10:g.114438517del`, `NC_000001.11:g.113895895del`, `NG_031901.1:g.14226del`, `NM_001253852.3:c.1655del`, `NM_001253853.3:c.1358del`, `NM_001308312.2:c.1151del`, `NM_006594.5:c.1655del`

## 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 0.122, GERP -4.19, phastCons 0.125 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.777, pLI 8.6664e-10. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 9 of 10**, 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}

**AP4B1** population constraint: LOEUF 0.777, pLI 8.6664e-10, missense-Z 0.49189; ClinGen dosage — haploinsufficiency 30, 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):

- **AP-4 deficiency syndrome** — Definitive (AR)

## Protein context {#protein}

Residue **552** lies in the 'hinge' region.

AlphaFold model confidence (whole protein): pLDDT 86.56, 64% of residues very-high.

**5 experimental structure(s)** (PDB): [2MJ7](https://www.rcsb.org/structure/2MJ7), [9U9I](https://www.rcsb.org/structure/9U9I), [9U9J](https://www.rcsb.org/structure/9U9J), [9U9R](https://www.rcsb.org/structure/9U9R), [9U9S](https://www.rcsb.org/structure/9U9S).

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

*Describes the biological roles of AP4B1 (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.*


### Pathways affected {#pathways}

AP4B1 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [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 |

## Clinical significance {#significance}

**Likely pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2020-10-01.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Yale Center for Mendelian Genomics, Yale University | Likely pathogenic | no assertion criteria provided | literature only | 2020-10-01 |

## Associated conditions {#conditions}

[Spastic paraplegia](https://sugi.bio/atlas/disease/spastic-paraplegia/).

**Reported phenotype names (ClinVar):** Spastic paraplegia.

## Similar variants {#similar}

Related AP4B1 variant pages (same residue, condition, or type): [AP4B1 p.Asn452fs](/variant/ap4b1-p-asn452fs), [AP4B1 p.Leu104fs](/variant/ap4b1-p-leu104fs), [AP4B1 p.Leu499fs](/variant/ap4b1-p-leu499fs), [AP4B1 p.Arg137Gly](/variant/ap4b1-p-arg137gly), [AP4B1 p.Gln331Ter](/variant/ap4b1-p-gln331ter), [AP4B1 p.Lys537fs](/variant/ap4b1-p-lys537fs), [AP4B1 p.Gln331fs](/variant/ap4b1-p-gln331fs), [AP4B1 p.Thr387fs](/variant/ap4b1-p-thr387fs).

### 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 1344780). 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.*