# NM_000482.4(APOA4):c.1105_1106del (p.Ser369fs)

https://sugi.bio/variant/apoa4-p-ser369fs

## Summary

**APOA4 p.Ser369fs (c.1105_1106del)** is classified **Uncertain significance** in APOA4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-20). Very rare (popmax 0.000593%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · very rare (popmax 0.000593%, nfe)

## For patients & families {#patients}

This is a change in the APOA4 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [APOA4](https://sugi.bio/atlas/gene/APOA4/) |
| Protein change (HGVS p.) | p.Ser369fs |
| Coding change (HGVS c.) | c.1105_1106del |
| MANE Select transcript | [NM_000482](https://www.ncbi.nlm.nih.gov/nuccore/NM_000482) |
| Variant type | Microsatellite |
| Location | chr11:116820952-116820953 (GRCh38) |
| ClinVar | [VCV4777040](https://www.ncbi.nlm.nih.gov/clinvar/variation/4777040/) |

**All HGVS expressions:** `NC_000011.10:g.116820953AG[2]`, `NC_000011.9:g.116691669AG[2]`, `NG_012044.1:g.7339TC[2]`, `NM_000482.4:c.1105_1106del`

## 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 1.375, GERP 6.46, phastCons 0.957 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.985, pLI 5.836e-07. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (3 of 3)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- CADD: **PHRED 21.6**. 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 microsatellite 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 **0.000593%** (nfe) · FAF95 0.000247% · FAF99 0.000159% · 7/1,180,022 in the highest group · 7/1,613,906 alleles overall — very rare (popmax 0.000593%, 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}

**APOA4** population constraint: LOEUF 0.985, pLI 5.836e-07, missense-Z -0.34517. *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):

- **autosomal dominant medullary cystic kidney disease with or without hyperuricemia** — Limited (AD)

## Protein context {#protein}

Residue **369** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 81.14, 43% of residues very-high.

**2 experimental structure(s)** (PDB): [3S84](https://www.rcsb.org/structure/3S84), [9HX4](https://www.rcsb.org/structure/9HX4).

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

*Describes the biological roles of APOA4 (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:** APOA4's established molecular role includes copper ion binding. p.Ser369fs falls in the disordered region.


### Pathways affected {#pathways}

APOA4 participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Amyloid fiber formation](https://reactome.org/content/detail/R-HSA-977225) | curated |
| [Chylomicron assembly](https://reactome.org/content/detail/R-HSA-8963888) | curated |
| [Chylomicron remodeling](https://reactome.org/content/detail/R-HSA-8963901) | curated |
| [Assembly of active LPL and LIPC lipase complexes](https://reactome.org/content/detail/R-HSA-8963889) | electronic |
| [Retinoid metabolism and transport](https://reactome.org/content/detail/R-HSA-975634) | electronic |

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

**Molecular function:** copper ion binding, lipid binding, antioxidant activity, phosphatidylcholine binding, identical protein binding, protein homodimerization activity.

**Biological process:** innate immune response in mucosa, lipid transport, response to lipid hydroperoxide, leukocyte cell-cell adhesion, cholesterol metabolic process, positive regulation of triglyceride catabolic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-04-20.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-04-20 |

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

## Similar variants {#similar}

Related APOA4 variant pages (same residue, condition, or type): [APOA4 c.*56TGTC[3]](/variant/apoa4-c-star-56tgtc-3), [APOA4 p.376QQEQ[2]](/variant/apoa4-p-376qqeq-2), [APOA4 p.Gln387_Val388insGlnGlnGluGln](/variant/apoa4-p-gln387-val388insglnglnglugln).

### 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 4777040). 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.*