# NM_000484.4(APP):c.1305C>T (p.Phe435=)

https://sugi.bio/variant/app-p-phe435

## Summary

**APP p.Phe435= (c.1305C>T)** is classified **Benign/Likely benign** in APP (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-14). Rare (popmax 0.165%, mid); Associated with Alzheimer disease.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs148180403 · 7 submitters · 1 linked condition · rare (popmax 0.165%, mid)

## For patients & families {#patients}

This is a change in the APP gene that is classified as benign/likely benign — not considered disease-causing, submitted by 7 submitters, and is linked to Alzheimer disease.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 3119 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | APP is a diagnostic-grade gene on 5 Genomics England panels |

**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.Phe435= |
| Coding change (HGVS c.) | c.1305C>T |
| MANE Select transcript | [NM_000484](https://www.ncbi.nlm.nih.gov/nuccore/NM_000484) |
| dbSNP | [rs148180403](https://www.ncbi.nlm.nih.gov/snp/rs148180403/) |
| Variant type | single nucleotide variant |
| Location | chr21:25975223-25975223 (GRCh38) |
| ClinVar | [VCV446854](https://www.ncbi.nlm.nih.gov/clinvar/variation/446854/) |

**All HGVS expressions:** `NC_000021.8:g.27347536G>A`, `NC_000021.9:g.25975223G>A`, `NG_007376.2:g.200906C>T`, `NM_000484.4:c.1305C>T`, `NM_001136016.3:c.1233C>T`, `NM_001136129.3:c.912C>T`, `NM_001136130.3:c.1137C>T`, `NM_001136131.3:c.975C>T`, `NM_001204301.2:c.1305C>T`, `NM_001204302.2:c.1248C>T`, `NM_001204303.2:c.1080C>T`, `NM_001385253.1:c.1137C>T`, `NM_201413.3:c.1248C>T`, `NM_201414.3:c.1080C>T`

## 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 0.21) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 8.689, GERP 1.86, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 16.38**. 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 **0.10**, donor loss **0.00**, acceptor gain **0.21**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.10**, donor loss **0.00**, acceptor gain **0.21**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.165%** (mid) · FAF95 0.0895% · FAF99 0.0839% · 10/6,062 in the highest group · 1,200/1,614,096 alleles overall — rare (popmax 0.165%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.165% | 606 |
| European (non-Finnish) | 0.0902% | 1,109 |
| Remaining individuals (not grpmax-eligible) | 0.0816% | 1,226 |
| Admixed American | 0.06% | 1,667 |
| South Asian | 0.0198% | 5,060 |
| African / African-American | 0.0187% | 5,360 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0101% | 9,868 |
| Finnish (not grpmax-eligible) | 0.00625% | 16,003 |

*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 **435** lies in the e2 domain; an α-helix.

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.Phe435= falls in the e2 domain. 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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-14.

**Submitter consensus:** conflicting (4 Likely benign, 3 Benign).

**Submission history:** 7 submissions (2018–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Likely benign | criteria provided, single submitter | clinical testing | 2018-01-12 |
| Athena Diagnostics | Benign | criteria provided, single submitter | clinical testing | 2021-04-13 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2022-04-17 |
| Mayo Clinic Laboratories, Mayo Clinic | Likely benign | criteria provided, single submitter | clinical testing | 2025-05-19 |
| CeGaT Center for Human Genetics Tuebingen | Benign | criteria provided, single submitter | clinical testing | 2025-10-01 |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-14 |

## Associated conditions {#conditions}

[Alzheimer disease](https://sugi.bio/atlas/disease/alzheimer-disease/).

**Reported phenotype names (ClinVar):** Alzheimer disease, not specified, APP-related disorder, not provided, AllHighlyPenetrant, none provided, APP-related condition, Presenile and senile dementia, Alzheimer's disease.

## Similar variants {#similar}

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

### 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 446854). 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.*