# NM_000484.4(APP):c.1810G>A (p.Val604Met)

https://sugi.bio/variant/app-p-val604met

## Summary

**APP p.Val604Met (c.1810G>A)** is classified **Conflicting classifications of pathogenicity** in APP (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-09-20). AlphaMissense: likely benign (0.0976); Ultra-rare (popmax 0.049%, eas); Associated with Alzheimer disease.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs199887707 · 4 submitters · 1 linked condition · AlphaMissense likely benign · ultra-rare (popmax 0.049%, eas)

## For patients & families {#patients}

This is a change in the APP gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 4 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.Val604Met |
| Coding change (HGVS c.) | c.1810G>A |
| MANE Select transcript | [NM_000484](https://www.ncbi.nlm.nih.gov/nuccore/NM_000484) |
| dbSNP | [rs199887707](https://www.ncbi.nlm.nih.gov/snp/rs199887707/) |
| Variant type | single nucleotide variant |
| Location | chr21:25911840-25911840 (GRCh38) |
| ClinVar | [VCV339632](https://www.ncbi.nlm.nih.gov/clinvar/variation/339632/) |

**All HGVS expressions:** `NC_000021.8:g.27284152C>T`, `NC_000021.9:g.25911840C>T`, `NG_007376.2:g.264289G>A`, `NM_000484.4:c.1810G>A`, `NM_001136016.3:c.1738G>A`, `NM_001136129.3:c.1417G>A`, `NM_001136130.3:c.1642G>A`, `NM_001136131.3:c.1480G>A`, `NM_001204301.2:c.1810G>A`, `NM_001204302.2:c.1753G>A`, `NM_001204303.2:c.1585G>A`, `NM_001385253.1:c.1642G>A`, `NM_201413.3:c.1753G>A`, `NM_201414.3:c.1585G>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.0976)
- REVEL 0.62 (indeterminate)
- SaProt LLR -7.412 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate
- Conservation: phyloP 7.66, GERP 1.76, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 24.3**. 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 **0.049%** (eas) · FAF95 0.0332% · FAF99 0.0279% · 22/44,868 in the highest group · 393/1,614,126 alleles overall — ultra-rare (popmax 0.049%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.269% | 372 |
| East Asian (grpmax) | 0.049% | 2,039 |
| Remaining individuals (not grpmax-eligible) | 0.0192% | 5,209 |
| Middle Eastern | 0.0165% | 6,062 |
| European (non-Finnish) | 0.0147% | 6,782 |
| South Asian | 0.011% | 9,108 |
| Admixed American | 0.00167% | 60,014 |
| African / African-American | 0.00133% | 75,032 |

Finnish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-09-20.

**Submitter consensus:** conflicting (2 Uncertain significance, 1 Benign, 1 Likely benign).

**Submission history:** 4 submissions (2018–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2025-09-20 |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-01-29 |
| CeGaT Center for Human Genetics Tuebingen | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-03-01 |

## Associated conditions {#conditions}

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

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

## 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 2026-10-14); 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 339632). 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.*