# NM_000132.4(F8):c.1555_1556dup (p.Asp519fs)

https://sugi.bio/variant/f8-p-asp519fs

## Summary

**F8 p.Asp519fs (c.1555_1556dup)** is classified **Pathogenic** in F8 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-23). No gnomAD frequency available for this variant.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2523942440 · 1 submitter · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the F8 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter.

*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 | [F8](https://sugi.bio/atlas/gene/F8/) |
| Protein change (HGVS p.) | p.Asp519fs |
| Coding change (HGVS c.) | c.1555_1556dup |
| MANE Select transcript | [NM_000132](https://www.ncbi.nlm.nih.gov/nuccore/NM_000132) |
| dbSNP | [rs2523942440](https://www.ncbi.nlm.nih.gov/snp/rs2523942440/) |
| Variant type | Duplication |
| Location | chrX:154957152-154957153 (GRCh38) |
| ClinVar | [VCV2428680](https://www.ncbi.nlm.nih.gov/clinvar/variation/2428680/) |

**All HGVS expressions:** `LRG_555:g.70570_70571dup`, `LRG_555t1:c.1555_1556dup`, `NC_000023.10:g.154185428_154185429dup`, `NC_000023.11:g.154957153_154957154dup`, `NG_011403.2:g.70570_70571dup`, `NM_000132.4:c.1555_1556dup`

## 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 1.114, GERP -1.33, phastCons 0.537 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene, supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 11 of 26**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**F8** population constraint: ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *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):

- **hemophilia A** — Definitive (XL)

## Protein context {#protein}

Residue **519** lies in the plastocyanin-like 3 domain; a turn; the f5/8 type a 2 domain.

AlphaFold model confidence (whole protein): pLDDT 61.20, 32% of residues very-high.

**29 experimental structure(s)** (PDB): [12JP](https://www.rcsb.org/structure/12JP), [12JV](https://www.rcsb.org/structure/12JV), [1CFG](https://www.rcsb.org/structure/1CFG), [1D7P](https://www.rcsb.org/structure/1D7P), [1FAC](https://www.rcsb.org/structure/1FAC), [1IQD](https://www.rcsb.org/structure/1IQD) — incl. mutant structure 9D5D.

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

*Describes the biological roles of F8 (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:** p.Asp519fs falls in the plastocyanin-like 3 domain. In Reactome, F8 is annotated in disease pathway(s) including **Defective F8 accelerates dissociation of the A2 domain**, **Defective F8 binding to the cell membrane**.

**Disease mechanism (Reactome):** F8 loss or alteration is curated in [Defective F8 accelerates dissociation of the A2 domain](https://reactome.org/content/detail/R-HSA-9672387), [Defective F8 binding to the cell membrane](https://reactome.org/content/detail/R-HSA-9672395), [Defective F8 binding to von Willebrand factor](https://reactome.org/content/detail/R-HSA-9672393).

### Pathways affected {#pathways}

F8 participates in **18 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective F8 accelerates dissociation of the A2 domain](https://reactome.org/content/detail/R-HSA-9672387) | curated |
| ⚕ [Defective F8 binding to the cell membrane](https://reactome.org/content/detail/R-HSA-9672395) | curated |
| ⚕ [Defective F8 binding to von Willebrand factor](https://reactome.org/content/detail/R-HSA-9672393) | curated |
| ⚕ [Defective F8 cleavage by thrombin](https://reactome.org/content/detail/R-HSA-9672391) | curated |
| ⚕ [Defective F8 secretion](https://reactome.org/content/detail/R-HSA-9672397) | curated |
| ⚕ [Defective F8 sulfation at Y1699](https://reactome.org/content/detail/R-HSA-9674519) | curated |
| ⚕ [Defective F9 variant does not activate FX](https://reactome.org/content/detail/R-HSA-9673202) | curated |
| ⚕ [Defective cofactor function of FVIIIa variant](https://reactome.org/content/detail/R-HSA-9672396) | curated |
| ⚕ [Defective factor IX causes thrombophilia](https://reactome.org/content/detail/R-HSA-9672383) | curated |
| [Amplification and propagation of coagulation cascade](https://reactome.org/content/detail/R-HSA-9769743) | curated |
| [COPII-mediated vesicle transport](https://reactome.org/content/detail/R-HSA-204005) | curated |
| [Cargo concentration in the ER](https://reactome.org/content/detail/R-HSA-5694530) | curated |
| [Gamma carboxylation, hypusinylation, hydroxylation, and arylsulfatase activation](https://reactome.org/content/detail/R-HSA-163841) | curated |
| [Initiation of coagulation cascade](https://reactome.org/content/detail/R-HSA-9769735) | curated |
| [Platelet degranulation ](https://reactome.org/content/detail/R-HSA-114608) | curated |
| [Regulation of clotting cascade](https://reactome.org/content/detail/R-HSA-9769739) | curated |
| [None](https://reactome.org/content/detail/R-HSA-140837) | other |
| [None](https://reactome.org/content/detail/R-HSA-140875) | other |

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-08-23.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Pathogenic | criteria provided, single submitter | clinical testing | 2022-08-23 |

**Reported phenotype names (ClinVar):** not provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM, none provided.

## Similar variants {#similar}

Related F8 variant pages (same residue, condition, or type): [F8 p.Asn982fs](/variant/f8-p-asn982fs), [F8 p.Glu1101fs](/variant/f8-p-glu1101fs), [F8 p.Leu2320fs](/variant/f8-p-leu2320fs), [F8 p.Thr1609fs](/variant/f8-p-thr1609fs), [F8 c.5374-19dup](/variant/f8-c-5374-minus-19dup), [F8 p.Ala1819fs](/variant/f8-p-ala1819fs), [F8 p.Arg1567fs](/variant/f8-p-arg1567fs), [F8 p.Asn358fs](/variant/f8-p-asn358fs).

### 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 2428680). 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.*