# NM_007347.5(AP4E1):c.993G>A (p.Ser331=)

https://sugi.bio/variant/ap4e1-p-ser331

## Summary

**AP4E1 p.Ser331= (c.993G>A)** is classified **Conflicting classifications of pathogenicity** in AP4E1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-06-30). Very rare (popmax 0.00483%, nfe).

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · 2 submitters · very rare (popmax 0.00483%, nfe)

## For patients & families {#patients}

This is a change in the AP4E1 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters.

*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.Ser331= |
| Coding change (HGVS c.) | c.993G>A |
| MANE Select transcript | [NM_007347](https://www.ncbi.nlm.nih.gov/nuccore/NM_007347) |
| Variant type | single nucleotide variant |
| Location | chr15:50941491-50941491 (GRCh38) |
| ClinVar | [VCV3342971](https://www.ncbi.nlm.nih.gov/clinvar/variation/3342971/) |

**All HGVS expressions:** `LRG_732:g.37820G>A`, `LRG_732t1:c.993G>A`, `NC_000015.10:g.50941491G>A`, `NC_000015.9:g.51233688G>A`, `NG_031875.2:g.37820G>A`, `NM_001252127.2:c.768G>A`, `NM_007347.5:c.993G>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.48) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -0.19, GERP -3.72, phastCons 0.006 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 16.36**. 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 deltas (raw): acceptor loss **0.17**, donor loss **0.00**, acceptor gain **0.48**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.48**, donor gain **0.00**.
- Pangolin: Δ**0.27** (loss), gain 0.10 / loss 0.27. SpliceAI calls gain. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00483%** (nfe) · FAF95 0.00378% · FAF99 0.00345% · 57/1,179,406 in the highest group · 62/1,612,724 alleles overall — very rare (popmax 0.00483%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00483% | 20,691 |
| Remaining individuals (not grpmax-eligible) | 0.00481% | 20,807 |
| East Asian | 0.00223% | 44,794 |
| African / African-American | 0.00134% | 74,856 |

*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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-06-30.

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

**Submission history:** 2 submissions (2023–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-04-04 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-06-30 |

**Reported phenotype names (ClinVar):** not provided, not specified, none provided, AllHighlyPenetrant.

## Similar variants {#similar}

Related AP4E1 variant pages (same residue, condition, or type): [AP4E1 p.Ser331Leu](/variant/ap4e1-p-ser331leu), [AP4E1 p.Arg1105Ter](/variant/ap4e1-p-arg1105ter), [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.Ala65Val](/variant/ap4e1-p-ala65val), [AP4E1 p.Ala678Val](/variant/ap4e1-p-ala678val).

### 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 3342971). 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.*