# NM_000484.4(APP):c.1963+8A>C

https://sugi.bio/variant/app-c-1963-plus-8a-c

## Summary

**APP c.1963+8A>C** is classified **Likely benign** in APP (ClinVar, No assertion criteria, 1 submitter; last evaluated 2023-05-08). Ultra-rare (popmax 0.0165%, mid); Associated with APP-related disorder.

**At a glance:** Likely benign · review: No assertion criteria · rsID rs2517062578 · 1 submitter · 1 linked condition · ultra-rare (popmax 0.0165%, mid)

## For patients & families {#patients}

This is a change in the APP gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to APP-related disorder.

*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/) |
| Coding change (HGVS c.) | c.1963+8A>C |
| MANE Select transcript | [NM_000484](https://www.ncbi.nlm.nih.gov/nuccore/NM_000484) |
| dbSNP | [rs2517062578](https://www.ncbi.nlm.nih.gov/snp/rs2517062578/) |
| Variant type | single nucleotide variant |
| Location | chr21:25905016-25905016 (GRCh38) |
| ClinVar | [VCV3036130](https://www.ncbi.nlm.nih.gov/clinvar/variation/3036130/) |

**All HGVS expressions:** `NC_000021.8:g.27277328T>G`, `NC_000021.9:g.25905016T>G`, `NG_007376.2:g.271113A>C`, `NM_000484.4:c.1963+8A>C`, `NM_001136016.3:c.1891+8A>C`, `NM_001136129.3:c.1570+8A>C`, `NM_001136130.3:c.1795+8A>C`, `NM_001136131.3:c.1633+8A>C`, `NM_001204301.2:c.1909+6725A>C`, `NM_001204302.2:c.1852+6725A>C`, `NM_001204303.2:c.1684+6725A>C`, `NM_001385253.1:c.1795+8A>C`, `NM_201413.3:c.1906+8A>C`, `NM_201414.3:c.1738+8A>C`

## 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 -0.238, GERP -3.54 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 0.527**. 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.*
- Splice region: **near-intronic (+8 nt from the splice site)**.
- Non-coding constraint (Gnocchi): **Z 0.90**, o/e 0.92 (1 kb window 25,905,000–25,906,000). A higher Z means the window carries less variation than expected. Describes the 1 kb window, not this allele. No ClinGen expert panel references Gnocchi and no ACMG-calibrated threshold exists for it. *Descriptive; no cut-point 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 **0.0165%** (mid) · FAF95 0.00153% · FAF99 0.0013% · 1/6,062 in the highest group · 30/1,613,146 alleles overall — ultra-rare (popmax 0.0165%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0165% | 6,062 |
| European (non-Finnish) | 0.0022% | 45,357 |
| South Asian | 0.0022% | 45,466 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,460 |

*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 0/3, triplosensitivity 1/3. *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}

**Likely benign** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2023-05-08.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2023-05-08 |

## Associated conditions {#conditions}

[APP-related disorder](https://sugi.bio/atlas/disease/app-related-disorder/).

**Reported phenotype names (ClinVar):** APP-related disorder, APP-related condition.

## Similar variants {#similar}

Related APP variant pages (same residue, condition, or type): [APP p.Leu723Pro](/variant/app-p-leu723pro), [APP p.Arg268Thr](/variant/app-p-arg268thr), [APP p.Glu605Gln](/variant/app-p-glu605gln), [APP p.His677Arg](/variant/app-p-his677arg), [APP p.Ile63Val](/variant/app-p-ile63val), [APP p.Thr276Ala](/variant/app-p-thr276ala), [APP p.Val715Ala](/variant/app-p-val715ala), [APP p.Ala479Ser](/variant/app-p-ala479ser).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 3036130). 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.*