# NM_000484.4(APP):c.13T>G (p.Leu5Val)

https://sugi.bio/variant/app-p-leu5val

## Summary

**APP p.Leu5Val (c.13T>G)** is classified **Uncertain significance** in APP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-30). AlphaMissense: likely benign (0.068); Very rare (popmax 0.00401%, nfe); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs1446208112 · 2 submitters · 2 linked conditions · AlphaMissense likely benign · very rare (popmax 0.00401%, nfe)

## For patients & families {#patients}

This is a change in the APP gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to Inborn genetic diseases.

*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 | [APP](https://sugi.bio/atlas/gene/APP/) |
| Protein change (HGVS p.) | p.Leu5Val |
| Coding change (HGVS c.) | c.13T>G |
| MANE Select transcript | [NM_000484](https://www.ncbi.nlm.nih.gov/nuccore/NM_000484) |
| dbSNP | [rs1446208112](https://www.ncbi.nlm.nih.gov/snp/rs1446208112/) |
| Variant type | single nucleotide variant |
| Location | chr21:26170608-26170608 (GRCh38) |
| ClinVar | [VCV2559949](https://www.ncbi.nlm.nih.gov/clinvar/variation/2559949/) |

**All HGVS expressions:** `NC_000021.8:g.27542926A>C`, `NC_000021.9:g.26170608A>C`, `NG_007376.2:g.5521T>G`, `NG_144137.2:g.728A>C`, `NM_000484.4:c.13T>G`, `NM_001136129.3:c.13T>G`, `NM_001136130.3:c.13T>G`, `NM_001136131.3:c.-49+377T>G`, `NM_001204301.2:c.13T>G`, `NM_001204302.2:c.13T>G`, `NM_001204303.2:c.13T>G`, `NM_001385253.1:c.13T>G`, `NM_201413.3:c.13T>G`, `NM_201414.3:c.13T>G`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.068)
- REVEL 0.127 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.468 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 1.15, GERP -2.87, phastCons 0.088 — weakly conserved position
- CADD: **PHRED 15.84**. 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.*
- Regional missense constraint: **o/e 0.84** across the covering region of the MANE Select transcript (25,881,673–26,170,620), spanning 288,947 bp. Chi-square p 2e-07. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (A>T, Δ0.47 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 **0.00401%** (nfe) · FAF95 0.00308% · FAF99 0.00275% · 46/1,146,098 in the highest group · 47/1,385,612 alleles overall — very rare (popmax 0.00401%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00401% | 24,915 |
| Remaining individuals (not grpmax-eligible) | 0.00167% | 59,894 |

*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}

**APP** population constraint: LOEUF 0.41, pLI 0.99999, missense-Z 2.2633; ClinGen dosage — haploinsufficiency 0, triplosensitivity 1 (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):

- **cerebral amyloid angiopathy, APP-related** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 68.11, 30% of residues very-high.

**263 experimental structure(s)** (PDB): [11EN](https://www.rcsb.org/structure/11EN), [11EO](https://www.rcsb.org/structure/11EO), [11EP](https://www.rcsb.org/structure/11EP), [12GB](https://www.rcsb.org/structure/12GB), [1AAP](https://www.rcsb.org/structure/1AAP), [1AMB](https://www.rcsb.org/structure/1AMB) — incl. mutant structure 23WM.

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

*Describes the biological roles of APP (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:** APP's established molecular role includes serine-type endopeptidase inhibitor activity. In Reactome, APP is annotated in disease pathway(s) including **Aggregated β-amyloid induces FXII autocatalysis**, **Aggregated β-amyloid interacts with fibrinogen**.

**Disease mechanism (Reactome):** APP loss or alteration is curated in [Aggregated β-amyloid induces FXII autocatalysis](https://reactome.org/content/detail/R-HSA-9936900), [Aggregated β-amyloid interacts with fibrinogen](https://reactome.org/content/detail/R-HSA-9936686), [Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models](https://reactome.org/content/detail/R-HSA-8862803).

### Pathways affected {#pathways}

APP participates in **20 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Aggregated β-amyloid induces FXII autocatalysis](https://reactome.org/content/detail/R-HSA-9936900) | curated |
| ⚕ [Aggregated β-amyloid interacts with fibrinogen](https://reactome.org/content/detail/R-HSA-9936686) | curated |
| ⚕ [Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models](https://reactome.org/content/detail/R-HSA-8862803) | curated |
| ⚕ [Purinergic signaling in leishmaniasis infection](https://reactome.org/content/detail/R-HSA-9660826) | curated |
| [Amyloid fiber formation](https://reactome.org/content/detail/R-HSA-977225) | curated |
| [ECM proteoglycans](https://reactome.org/content/detail/R-HSA-3000178) | curated |
| [Formyl peptide receptors bind formyl peptides and many other ligands](https://reactome.org/content/detail/R-HSA-444473) | curated |
| [G alpha (i) signalling events](https://reactome.org/content/detail/R-HSA-418594) | curated |
| [G alpha (q) signalling events](https://reactome.org/content/detail/R-HSA-416476) | curated |
| [Lysosome Vesicle Biogenesis](https://reactome.org/content/detail/R-HSA-432720) | curated |
| [Platelet degranulation ](https://reactome.org/content/detail/R-HSA-114608) | curated |
| [Post-translational protein phosphorylation](https://reactome.org/content/detail/R-HSA-8957275) | curated |
| [Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)](https://reactome.org/content/detail/R-HSA-381426) | curated |
| [Regulation of clotting cascade](https://reactome.org/content/detail/R-HSA-9769739) | curated |
| [TAK1-dependent IKK and NF-kappa-B activation  ](https://reactome.org/content/detail/R-HSA-445989) | curated |
| [TRAF6 mediated NF-kB activation](https://reactome.org/content/detail/R-HSA-933542) | curated |
| [The NLRP3 inflammasome](https://reactome.org/content/detail/R-HSA-844456) | curated |
| [Advanced glycosylation endproduct receptor signaling](https://reactome.org/content/detail/R-HSA-879415) | electronic |
| [Insertion of tail-anchored proteins into the endoplasmic reticulum membrane](https://reactome.org/content/detail/R-HSA-9609523) | electronic |
| [Mitochondrial protein degradation](https://reactome.org/content/detail/R-HSA-9837999) | other |

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

**Molecular function:** serine-type endopeptidase inhibitor activity, signaling receptor binding, enzyme binding, identical protein binding, receptor ligand activity, PTB domain binding.

**Biological process:** microglial cell activation, astrocyte activation involved in immune response, learning or memory, learning, negative regulation of cell population proliferation, regulation of gene expression.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-01-30.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2023–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-06-13 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-01-30 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/), [Alzheimer disease](https://sugi.bio/atlas/disease/alzheimer-disease/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, Alzheimer disease, Presenile and senile dementia, Alzheimer's disease.

## Similar variants {#similar}

Related APP variant pages (same residue, condition, or type): [APP p.Leu5Phe](/variant/app-p-leu5phe), [APP p.Ala713Thr](/variant/app-p-ala713thr), [APP p.Asp694Asn](/variant/app-p-asp694asn), [APP p.Glu693Gln](/variant/app-p-glu693gln), [APP p.Ile716Phe](/variant/app-p-ile716phe), [APP p.Thr714Ala](/variant/app-p-thr714ala), [APP p.Val715Met](/variant/app-p-val715met), [APP p.Val717Ile](/variant/app-p-val717ile).

### 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 2559949). 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.*