# NM_007347.5(AP4E1):c.1290C>T (p.Val430=)

https://sugi.bio/variant/ap4e1-p-val430

## Summary

**AP4E1 p.Val430= (c.1290C>T)** is classified **Likely benign** in AP4E1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-17). Ultra-rare (popmax 0.0329%, mid); Associated with Spastic paraplegia.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs767875770 · 2 submitters · 1 linked condition · ultra-rare (popmax 0.0329%, mid)

## For patients & families {#patients}

This is a change in the AP4E1 gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters, 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 | [AP4E1](https://sugi.bio/atlas/gene/AP4E1/) |
| Protein change (HGVS p.) | p.Val430= |
| Coding change (HGVS c.) | c.1290C>T |
| MANE Select transcript | [NM_007347](https://www.ncbi.nlm.nih.gov/nuccore/NM_007347) |
| dbSNP | [rs767875770](https://www.ncbi.nlm.nih.gov/snp/rs767875770/) |
| Variant type | single nucleotide variant |
| Location | chr15:50948133-50948133 (GRCh38) |
| ClinVar | [VCV1628290](https://www.ncbi.nlm.nih.gov/clinvar/variation/1628290/) |

**All HGVS expressions:** `LRG_732:g.44462C>T`, `LRG_732t1:c.1290C>T`, `NC_000015.10:g.50948133C>T`, `NC_000015.9:g.51240330C>T`, `NG_031875.2:g.44462C>T`, `NM_001252127.2:c.1065C>T`, `NM_007347.5:c.1290C>T`

## 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 2.875, GERP -1.14, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 11.05**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.77 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0329%** (mid) · FAF95 0.0058% · FAF99 0.00241% · 2/6,080 in the highest group · 41/1,613,720 alleles overall — ultra-rare (popmax 0.0329%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0329% | 3,040 |
| Admixed American | 0.00833% | 11,999 |
| European (non-Finnish) | 0.00254% | 39,331 |
| South Asian | 0.0022% | 45,526 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,476 |
| African / African-American | 0.00134% | 74,886 |

*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}

**AP4E1** population constraint: LOEUF 0.576, pLI 0.00043414, missense-Z 0.36717. *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 72.42, 25% of residues very-high.

**4 experimental structure(s)** (PDB): [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 AP4E1 (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}

AP4E1 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 benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-04-17.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2024–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-04-17 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-03-13 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Spastic paraplegia, not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related AP4E1 variant pages (same residue, condition, or type): [AP4E1 p.Arg304Ter](/variant/ap4e1-p-arg304ter), [AP4E1 p.Ala119Ser](/variant/ap4e1-p-ala119ser), [AP4E1 p.Ala45Thr](/variant/ap4e1-p-ala45thr), [AP4E1 p.Ala475Val](/variant/ap4e1-p-ala475val), [AP4E1 p.Arg646Cys](/variant/ap4e1-p-arg646cys), [AP4E1 p.Asn1086Ser](/variant/ap4e1-p-asn1086ser), [AP4E1 p.Asp484Val](/variant/ap4e1-p-asp484val), [AP4E1 p.Asp938Gly](/variant/ap4e1-p-asp938gly).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2026-10-14); 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 1628290). 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.*