# NM_000484.4(APP):c.2149G>A (p.Val717Ile)

https://sugi.bio/variant/app-p-val717ile

## Summary

**APP p.Val717Ile (c.2149G>A)** is classified **Pathogenic** in APP (ClinVar, Multiple submitters, 12 submitters; last evaluated 2025-11-28). AlphaMissense: likely benign (0.1028); Very rare (popmax 0.00017%, nfe); Associated with Alzheimer disease type 1.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs63750264 · 12 submitters · 3 linked conditions · AlphaMissense likely benign · very rare (popmax 0.00017%, nfe)

## For patients & families {#patients}

This is a change in the APP gene that is reported as disease-causing, though the computational evidence is not fully concordant, submitted by 12 submitters, and is linked to Alzheimer disease type 1.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | Adult |
| Prevalence | 1-9 / 100 000 (Europe) |
| Clinical trials | 23 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | APP is a diagnostic-grade gene on 5 Genomics England panels |

**Commonly reported features of Early-onset autosomal dominant Alzheimer disease** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Agitation — Very frequent (99-80%)
- Dementia — Very frequent (99-80%)
- Hallucinations — Very frequent (99-80%)
- Seizure — Very frequent (99-80%)
- Hypertonia — Very frequent (99-80%)
- Confusion — Very frequent (99-80%)
- Parkinsonism — Very frequent (99-80%)
- Myoclonus — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0009465/index) · [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.Val717Ile |
| Coding change (HGVS c.) | c.2149G>A |
| MANE Select transcript | [NM_000484](https://www.ncbi.nlm.nih.gov/nuccore/NM_000484) |
| dbSNP | [rs63750264](https://www.ncbi.nlm.nih.gov/snp/rs63750264/) |
| Variant type | single nucleotide variant |
| Location | chr21:25891784-25891784 (GRCh38) |
| ClinVar | [VCV18088](https://www.ncbi.nlm.nih.gov/clinvar/variation/18088/) |

**All HGVS expressions:** `NC_000021.8:g.27264096C>T`, `NC_000021.9:g.25891784C>T`, `NG_007376.2:g.284345G>A`, `NM_000484.4:c.2149G>A`, `NM_001136016.3:c.2077G>A`, `NM_001136129.3:c.1756G>A`, `NM_001136130.3:c.1981G>A`, `NM_001136131.3:c.1819G>A`, `NM_001204301.2:c.2095G>A`, `NM_001204302.2:c.2038G>A`, `NM_001204303.2:c.1870G>A`, `NM_001385253.1:c.1981G>A`, `NM_201413.3:c.2092G>A`, `NM_201414.3:c.1924G>A`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — AlphaMissense predicts likely-benign.

- AlphaMissense **likely benign** (0.1028) — ⚠ discordant with the pathogenic call
- REVEL 0.78 (moderately pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -6.265 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** REVEL calls this damaging; AlphaMissense and SaProt do not
- Conservation: phyloP 7.613, GERP 1.93, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 26.8**. 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: **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 **0.00017%** (nfe) · FAF95 2.8e-05% · FAF99 1.1e-05% · 2/1,179,800 in the highest group · 2/1,613,870 alleles overall — very rare (popmax 0.00017%, 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}

**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}

Residue **717** lies in a UniProt-annotated variant site (in ad1; increased amyloid-beta protein 42/40 ratio); a UniProt-annotated variant site (in ad1); a turn; the 'interaction with psen1' region.

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. p.Val717Ile falls in the interaction with psen1 region. 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}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-11-28.

**Submitter consensus:** conflicting (9 Pathogenic, 2 not provided, 1 pathogenic).

**Submission history:** 12 submissions (1996–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 1996-10-23 |
| GeneReviews | not provided | no classification provided | literature only |  |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-02-22 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-11-28 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-08-21 |
| VIB  Department of Molecular Genetics, University of Antwerp | not provided | no classification provided | not provided |  |
| Fulgent Genetics, Fulgent Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2021-12-10 |
| Clinical Genetics Laboratory, Skane University Hospital Lund | Pathogenic | criteria provided, single submitter | clinical testing | 2022-07-13 |
| Athena Diagnostics | pathogenic | criteria provided, single submitter | clinical testing | 2025-09-24 |
| CeGaT Center for Human Genetics Tuebingen | Pathogenic | criteria provided, single submitter | clinical testing | 2017-06-01 |
| Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Pathogenic | criteria provided, single submitter | clinical testing | 2025-06-16 |
| Neuberg Centre For Genomic Medicine, NCGM | Pathogenic | criteria provided, single submitter | clinical testing |  |

## Associated conditions {#conditions}

[Alzheimer disease type 1](https://sugi.bio/atlas/disease/alzheimer-disease-type-1/), [Alzheimer disease](https://sugi.bio/atlas/disease/alzheimer-disease/), [cerebral amyloid angiopathy, APP-related](https://sugi.bio/atlas/disease/cerebral-amyloid-angiopathy-app-related/).

**Reported phenotype names (ClinVar):** Alzheimer disease type 1, Alzheimer disease, not provided, Cerebral amyloid angiopathy, APP-related, APP-related disorder, ALZHEIMER DISEASE, FAMILIAL, 1, ALZHEIMER DISEASE, FAMILIAL, 1, AUTOSOMAL RECESSIVE, AMYLOIDOSIS, CEREBROARTERIAL, APP-RELATED, Cerebral amyloid angiopathy, Dutch, Italian, Iowa, Flemish, Arctic variants, APP-related condition.

## Same-residue context {#hotspot}

Residue **717** carries **3 other pathogenic ClinVar variants** — a recurrently-mutated position: [APP p.Val717Phe](/variant/app-p-val717phe), [APP p.Val717Gly](/variant/app-p-val717gly), [APP p.Val717Leu](/variant/app-p-val717leu). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related APP variant pages (same residue, condition, or type): [APP p.Val717Phe](/variant/app-p-val717phe), [APP p.Val717Gly](/variant/app-p-val717gly), [APP p.Val717Leu](/variant/app-p-val717leu), [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).

### 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 18088). 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.*