# NM_004722.4(AP4M1):c.142del (p.Val48fs)

https://sugi.bio/variant/ap4m1-p-val48fs

## Summary

**AP4M1 p.Val48fs (c.142del)** is classified **Pathogenic/Likely pathogenic** in AP4M1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-06-02). Very rare (popmax 0.00237%, nfe); Associated with hereditary spastic paraplegia 50.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs764326593 · 3 submitters · 1 linked condition · very rare (popmax 0.00237%, nfe)

## For patients & families {#patients}

This is a change in the AP4M1 gene that is considered likely disease-causing, submitted by 3 submitters, and is linked to hereditary spastic paraplegia 50.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Infancy, Neonatal |
| Clinical trials | 4 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | AP4M1 is a diagnostic-grade gene on 7 Genomics England panels |

**Commonly reported features of Severe intellectual disability and progressive spastic paraplegia** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Microcephaly — Very frequent (99-80%)
- Hypotonia — Very frequent (99-80%)
- Progressive spastic paraplegia — Very frequent (99-80%)
- Intellectual disability, severe — Very frequent (99-80%)
- Coarse facial features — Frequent (79-30%)
- Facial hypotonia — Frequent (79-30%)
- Bulbous nose — Frequent (79-30%)
- Spasticity — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015592/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [AP4M1](https://sugi.bio/atlas/gene/AP4M1/) |
| Protein change (HGVS p.) | p.Val48fs |
| Coding change (HGVS c.) | c.142del |
| MANE Select transcript | [NM_004722](https://www.ncbi.nlm.nih.gov/nuccore/NM_004722) |
| dbSNP | [rs764326593](https://www.ncbi.nlm.nih.gov/snp/rs764326593/) |
| Variant type | Deletion |
| Location | chr7:100101963-100101963 (GRCh38) |
| ClinVar | [VCV1697248](https://www.ncbi.nlm.nih.gov/clinvar/variation/1697248/) |

**All HGVS expressions:** `NC_000007.13:g.99699586del`, `NC_000007.14:g.100101963del`, `NG_016312.1:g.5457del`, `NM_001363671.2:c.142del`, `NM_004722.4:c.142del`

## 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 4.879, GERP 2.1, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.106, pLI 5.0074e-18. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 15**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 35.0**. 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.*
- 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 (gnomAD v4.1): grpmax **0.00237%** (nfe) · FAF95 0.00165% · FAF99 0.00142% · 28/1,179,914 in the highest group · 28/1,613,046 alleles overall — very rare (popmax 0.00237%, 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}

**AP4M1** population constraint: LOEUF 1.106, pLI 5.0074e-18, missense-Z -0.18504. *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}


AlphaFold model confidence (whole protein): pLDDT 86.16, 64% of residues very-high.

**6 experimental structure(s)** (PDB): [3L81](https://www.rcsb.org/structure/3L81), [4MDR](https://www.rcsb.org/structure/4MDR), [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) — incl. mutant structure 4MDR.

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

*Describes the biological roles of AP4M1 (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:** AP4M1's established molecular role includes protein domain specific binding.


### Pathways affected {#pathways}

AP4M1 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Lysosome Vesicle Biogenesis](https://reactome.org/content/detail/R-HSA-432720) | curated |

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

**Molecular function:** protein domain specific binding.

**Biological process:** autophagosome assembly, protein targeting, protein targeting to lysosome, intracellular protein transport, Golgi to endosome transport, Golgi to lysosome transport.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-06-02.

**Submitter consensus:** conflicting (2 Pathogenic, 1 Likely pathogenic).

**Submission history:** 3 submissions (2022–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Institute of Human Genetics, University of Goettingen | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-07-18 |
| Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Pathogenic | criteria provided, single submitter | clinical testing | 2025-06-02 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-11-05 |

## Associated conditions {#conditions}

[hereditary spastic paraplegia 50](https://sugi.bio/atlas/disease/hereditary-spastic-paraplegia-50/).

**Reported phenotype names (ClinVar):** Hereditary spastic paraplegia 50, Spastic paraplegia 50, autosomal recessive.

## Similar variants {#similar}

Related AP4M1 variant pages (same residue, condition, or type): [AP4M1 p.Lys11fs](/variant/ap4m1-p-lys11fs), [AP4M1 c.52_58+6del](/variant/ap4m1-c-52-58-plus-6del), [AP4M1 c.58+1_58+2del](/variant/ap4m1-c-58-plus-1-58-plus-2del), [AP4M1 c.607-2_607-1del](/variant/ap4m1-c-607-minus-2-607-minus-1del), [AP4M1 p.Arg338fs](/variant/ap4m1-p-arg338fs), [AP4M1 p.Asn185fs](/variant/ap4m1-p-asn185fs), [AP4M1 p.Asp190fs](/variant/ap4m1-p-asp190fs), [AP4M1 p.Asp43fs](/variant/ap4m1-p-asp43fs).

### 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 1697248). 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.*