# NM_001253852.3(AP4B1):c.992_999del (p.Gln331fs)

https://sugi.bio/variant/ap4b1-p-gln331fs

## Summary

**AP4B1 p.Gln331fs (c.992_999del)** is classified **Pathogenic/Likely pathogenic** in AP4B1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-10-22). Very rare (popmax 0.00246%, nfe); Associated with hereditary spastic paraplegia 47.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs773840258 · 4 submitters · 1 linked condition · very rare (popmax 0.00246%, nfe)

## For patients & families {#patients}

This is a change in the AP4B1 gene that is considered likely disease-causing, submitted by 4 submitters, and is linked to hereditary spastic paraplegia 47.

*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 | 2 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | AP4B1 is a diagnostic-grade gene on 9 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/0015749/index) · [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.Gln331fs |
| Coding change (HGVS c.) | c.992_999del |
| MANE Select transcript | [NM_001253852](https://www.ncbi.nlm.nih.gov/nuccore/NM_001253852) |
| dbSNP | [rs773840258](https://www.ncbi.nlm.nih.gov/snp/rs773840258/) |
| Variant type | Deletion |
| Location | chr1:113900019-113900026 (GRCh38) |
| ClinVar | [VCV2578580](https://www.ncbi.nlm.nih.gov/clinvar/variation/2578580/) |

**All HGVS expressions:** `LRG_1219:g.401_408del`, `NC_000001.10:g.114442641_114442648del`, `NC_000001.11:g.113900019_113900026del`, `NG_031901.1:g.10094_10101del`, `NG_057565.1:g.401_408del`, `NM_001253852.3:c.992_999del`, `NM_001253853.3:c.695_702del`, `NM_001308312.2:c.488_495del`, `NM_006594.5:c.992_999del`, `NM_006594.5:c.992_999delAGAAAGTG`, `NR_037864.1:n.516_523del`, `NR_125965.1:n.684_691del`

## 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 7.649, GERP 2.25, phastCons 1 — highly conserved position (PP3-type support)
- 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 5 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 (gnomAD v4.1): grpmax **0.00246%** (nfe) · FAF95 0.00172% · FAF99 0.00149% · 29/1,180,032 in the highest group · 33/1,461,894 alleles overall — very rare (popmax 0.00246%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,836 |
| European (non-Finnish) (grpmax) | 0.00246% | 40,691 |
| African / African-American | 0.00133% | 75,038 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}


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}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-10-22.

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

**Submission history:** 4 submissions (2022–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-04-25 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-10-22 |
| CeGaT Center for Human Genetics Tuebingen | Pathogenic | criteria provided, single submitter | clinical testing | 2023-07-01 |
| Blueprint Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-02-10 |

## Associated conditions {#conditions}

[hereditary spastic paraplegia 47](https://sugi.bio/atlas/disease/hereditary-spastic-paraplegia-47/).

**Reported phenotype names (ClinVar):** Hereditary spastic paraplegia 47, not provided, AP4B1-related disorder, none provided, adaptor protein 4 (AP-4) deficiency syndrome, CEREBRAL PALSY, SPASTIC QUADRIPLEGIC, 5, Spastic paraplegia 47, autosomal recessive, AP4B1-related condition.

## Same-residue context {#hotspot}

Residue **331** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [AP4B1 p.Gln331Ter](/variant/ap4b1-p-gln331ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related AP4B1 variant pages (same residue, condition, or type): [AP4B1 p.Thr387fs](/variant/ap4b1-p-thr387fs), [AP4B1 p.Tyr135_Arg137delinsTer](/variant/ap4b1-p-tyr135-arg137delinster), [AP4B1 c.1106_1114+8del](/variant/ap4b1-c-1106-1114-plus-8del), [AP4B1 p.Ala105fs](/variant/ap4b1-p-ala105fs), [AP4B1 p.Arg497fs](/variant/ap4b1-p-arg497fs), [AP4B1 p.Cys356fs](/variant/ap4b1-p-cys356fs), [AP4B1 p.Gly309fs](/variant/ap4b1-p-gly309fs), [AP4B1 p.Gly515fs](/variant/ap4b1-p-gly515fs).

### 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 2578580). 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.*