# NM_014855.3(AP5Z1):c.1464G>A (p.Pro488=)

https://sugi.bio/variant/ap5z1-p-pro488

## Summary

**AP5Z1 p.Pro488= (c.1464G>A)** is classified **Conflicting classifications of pathogenicity** in AP5Z1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-11-24). Rare (popmax 0.383%, sas); Associated with hereditary spastic paraplegia 48.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs376913055 · 3 submitters · 1 linked condition · rare (popmax 0.383%, sas)

## For patients & families {#patients}

This is a change in the AP5Z1 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 3 submitters, and is linked to hereditary spastic paraplegia 48.

*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) | Adult |
| Diagnostic panels | AP5Z1 is a diagnostic-grade gene on 4 Genomics England panels |

**Commonly reported features of Autosomal recessive spastic paraplegia type 48** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Hypoplasia of the corpus callosum — Very frequent (99-80%)
- Progressive spastic paraplegia — Very frequent (99-80%)
- Urinary incontinence — Frequent (79-30%)
- Intellectual disability — Frequent (79-30%)
- Ataxia — Frequent (79-30%)
- Myoclonus — Frequent (79-30%)
- Hyperreflexia — Frequent (79-30%)
- Lower limb spasticity — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017378/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [AP5Z1](https://sugi.bio/atlas/gene/AP5Z1/) |
| Protein change (HGVS p.) | p.Pro488= |
| Coding change (HGVS c.) | c.1464G>A |
| MANE Select transcript | [NM_014855](https://www.ncbi.nlm.nih.gov/nuccore/NM_014855) |
| dbSNP | [rs376913055](https://www.ncbi.nlm.nih.gov/snp/rs376913055/) |
| Variant type | single nucleotide variant |
| Location | chr7:4788163-4788163 (GRCh38) |
| ClinVar | [VCV696513](https://www.ncbi.nlm.nih.gov/clinvar/variation/696513/) |

**All HGVS expressions:** `LRG_1247:g.17533G>A`, `LRG_1247t1:c.1464G>A`, `NC_000007.13:g.4827794G>A`, `NC_000007.14:g.4788163G>A`, `NG_028111.1:g.17533G>A`, `NM_001364858.1:c.996G>A`, `NM_014855.3:c.1464G>A`, `NR_157345.1:n.1595G>A`

## 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 -4.419, GERP -2.38 — fast-evolving / accelerated position
- CADD: **PHRED 0.205**. 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** — 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 **0.383%** (sas) · FAF95 0.348% · FAF99 0.335% · 322/84,166 in the highest group · 398/1,552,598 alleles overall — rare (popmax 0.383%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.383% | 261 |
| Middle Eastern | 0.0438% | 2,285 |
| Remaining individuals (not grpmax-eligible) | 0.0333% | 3,003 |
| African / African-American | 0.00682% | 14,669 |
| European (non-Finnish) | 0.00426% | 23,447 |

*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}

**AP5Z1** population constraint: LOEUF 1.641, pLI 1.001e-47, missense-Z -6.1066. *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):

- **hereditary spastic paraplegia** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 85.32, 56% of residues very-high.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-11-24.

**Submitter consensus:** conflicting (1 Uncertain significance, 1 Benign, 1 Likely benign).

**Submission history:** 3 submissions (2018–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-12 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2025-11-24 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-10-08 |

## Associated conditions {#conditions}

[hereditary spastic paraplegia 48](https://sugi.bio/atlas/disease/hereditary-spastic-paraplegia-48/).

**Reported phenotype names (ClinVar):** Hereditary spastic paraplegia 48, not specified, AllHighlyPenetrant, SPASTIC PARAPLEGIA 48, AUTOSOMAL RECESSIVE, Spastic paraplegia 48.

## Similar variants {#similar}

Related AP5Z1 variant pages (same residue, condition, or type): [AP5Z1 p.Pro488Leu](/variant/ap5z1-p-pro488leu), [AP5Z1 c.1312-2A>G](/variant/ap5z1-c-1312-minus-2a-g), [AP5Z1 c.1707+1G>A](/variant/ap5z1-c-1707-plus-1g-a), [AP5Z1 c.1806-1G>C](/variant/ap5z1-c-1806-minus-1g-c), [AP5Z1 p.Arg138Ter](/variant/ap5z1-p-arg138ter), [AP5Z1 p.Arg310Ter](/variant/ap5z1-p-arg310ter), [AP5Z1 p.Arg311Ter](/variant/ap5z1-p-arg311ter), [AP5Z1 p.Arg345Ter](/variant/ap5z1-p-arg345ter).

### 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 696513). 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.*