# NM_000132.4(F8):c.6046C>T (p.Arg2016Trp)

https://sugi.bio/variant/f8-p-arg2016trp

## Summary

**F8 p.Arg2016Trp (c.6046C>T)** is classified **Pathogenic** in F8 (ClinVar, Expert panel, 8 submitters; last evaluated 2024-02-02). AlphaMissense: ambiguous (0.4219); Very rare (popmax 0.000112%, nfe); Associated with hemophilia A.

**At a glance:** Pathogenic · review: Expert panel · rsID rs137852453 · 8 submitters · 1 linked condition · AlphaMissense ambiguous · very rare (popmax 0.000112%, nfe)

## For patients & families {#patients}

This is a change in the F8 gene that is considered disease-causing, submitted by 8 submitters, and is linked to hemophilia A.

*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) | X-linked recessive |
| Age of onset (of this condition) | Childhood, Infancy, Neonatal |
| Prevalence | 1-9 / 100 000 (Worldwide) |
| Clinical trials | 482 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | F8 is a diagnostic-grade gene on 3 Genomics England panels |

**Commonly reported features of Hemophilia A** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Joint swelling — Very frequent (99-80%)
- Arthralgia — Very frequent (99-80%)
- Reduced factor VIII activity — Very frequent (99-80%)
- Bleeding with minor or no trauma — Very frequent (99-80%)
- Thromboembolism — Frequent (79-30%)
- Spontaneous hematomas — Frequent (79-30%)
- Oral cavity bleeding — Frequent (79-30%)
- Joint hemorrhage — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006591/index) · [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.Arg2016Trp |
| Coding change (HGVS c.) | c.6046C>T |
| MANE Select transcript | [NM_000132](https://www.ncbi.nlm.nih.gov/nuccore/NM_000132) |
| dbSNP | [rs137852453](https://www.ncbi.nlm.nih.gov/snp/rs137852453/) |
| Variant type | single nucleotide variant |
| Location | chrX:154902120-154902120 (GRCh38) |
| ClinVar | [VCV10304](https://www.ncbi.nlm.nih.gov/clinvar/variation/10304/) |

**All HGVS expressions:** `LRG_555:g.125604C>T`, `LRG_555t1:c.6046C>T`, `NC_000023.10:g.154130395G>A`, `NC_000023.11:g.154902120G>A`, `NG_011403.2:g.125604C>T`, `NM_000132.4:c.6046C>T`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL and SaProt both call this damaging; AlphaMissense is indeterminate — descriptive only.

- AlphaMissense **ambiguous** (0.4219) — no call either way
- REVEL 0.822 (moderately pathogenic-leaning)
- SaProt LLR -11.064 (damaging)
- → **In-silico consensus:** REVEL and SaProt both call this damaging; AlphaMissense is indeterminate
- Conservation: phyloP 1.946, GERP -0.219, phastCons 1 — weakly conserved position
- CADD: **PHRED 23.1**. 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 0.65** across the covering region of the MANE Select transcript (154,837,600–154,928,668), spanning 91,068 bp. Chi-square p 1.5e-14. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.40 acceptor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Pangolin: Δ**0.38** (loss), gain 0.01 / loss 0.38. SpliceAI below 0.2. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.000112%** (nfe) · 1/894,097 in the highest group · 1/1,210,019 alleles overall — very rare (popmax 0.000112%, 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}

**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 **2016** lies in the f5/8 type a 3 domain; the plastocyanin-like 6 domain; a UniProt-annotated variant site (in hema; severe familial); a UniProt-annotated variant site (in hema; severe/moderate/mild); a β-strand.

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.Arg2016Trp falls in the f5/8 type a 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 Expert panel *(reviewed by expert panel)*, last evaluated 2024-02-02.

**Submitter consensus:** unanimous (7/7 Pathogenic).

**Submission history:** 8 submissions (1995–2025); classifications have differed over time.

**ClinGen expert panel:** Pathogenic — Coagulation Factor Deficiency VCEP (hemophilia A). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PP4_Moderate`, `PM2_Supporting`, `PS4_VeryStrong`, `PP3`.
Inheritance: X-linked inheritance.

> **Curation rationale (ClinGen, verbatim):** The c.6046C>T (p.Arg2016Trp) variant is completely absent from gnomAD v2.1.1 and gnomAD v3 meeting PM2_Supporting. This missense variant has a REVEL score of 0.822 (>0.6) meeting PP3 criteria. More than 46 probands are reported with the variant and moderate-severe hemophilia A in the literature and internal laboratory data (PMID: 29296726, 20102490, 18387975), meeting F8 phenotype criteria. This variant has been associated with discrepant factor VIII activity levels (PMID: 32232366). This variant has also been reported in individuals with a history of inhibitor development to factor replacement therapy (EAHAD database). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8: PS4_Very Strong, PP4_Moderate, PP3, PM2_Supporting.
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50041 · approved 2024-02-02 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/3d921025-1d2e-41c3-9200-a2d11c4ad044).*
*These are ClinGen's applied codes, reported verbatim — Sugi Variant does not re-tally or combine them into its own classification.*

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 1995-01-01 |
| ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen | Pathogenic | reviewed by expert panel | curation | 2024-02-02 |
| Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico | Pathogenic | no assertion criteria provided | clinical testing | 2019-06-01 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Pathogenic | criteria provided, single submitter | clinical testing | 2018-07-22 |
| Myriad Genetics, Inc. | Pathogenic | criteria provided, single submitter | clinical testing | 2025-01-14 |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |
| North West Genomic Laboratory Hub, Manchester University NHS Foundation Trust | Pathogenic | criteria provided, single submitter | clinical testing | 2024-08-07 |
| Genetics and Molecular Pathology, SA Pathology | Pathogenic | criteria provided, single submitter | clinical testing | 2020-10-01 |

## Associated conditions {#conditions}

[hemophilia A](https://sugi.bio/atlas/disease/hemophilia-a/).

**Reported phenotype names (ClinVar):** Hereditary factor VIII deficiency disease, Thyroid cancer, nonmedullary, 1, Factor VIII deficiency, AUTOSOMAL HEMOPHILIA A, Hemophilia A, HEMOPHILIA, CLASSIC, Hemophilia A, congenital, HEM A, Factor 8 deficiency, congenital.

## Same-residue context {#hotspot}

Residue **2016** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [F8 p.Arg2016Gln](/variant/f8-p-arg2016gln). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related F8 variant pages (same residue, condition, or type): [F8 p.Arg2016Gln](/variant/f8-p-arg2016gln), [F8 c.6429+2T>A](/variant/f8-c-6429-plus-2t-a), [F8 p.Ala111Thr](/variant/f8-p-ala111thr), [F8 p.Ala2220Pro](/variant/f8-p-ala2220pro), [F8 p.Ala415Asp](/variant/f8-p-ala415asp), [F8 p.Ala415Val](/variant/f8-p-ala415val), [F8 p.Arg1768His](/variant/f8-p-arg1768his), [F8 p.Arg1800His](/variant/f8-p-arg1800his).

### 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 10304). 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.*