# NM_000132.4(F8):c.935T>C (p.Phe312Ser)

https://sugi.bio/variant/f8-p-phe312ser

## Summary

**F8 p.Phe312Ser (c.935T>C)** is classified **Pathogenic/Likely pathogenic** in F8 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-03-12). AlphaMissense: likely pathogenic (0.7711); Very rare (popmax 0.000112%, nfe); Associated with hemophilia B.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs137852405 · 6 submitters · 2 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 0.000112%, nfe)

## For patients & families {#patients}

This is a change in the F8 gene that is considered likely disease-causing, submitted by 6 submitters, and is linked to hemophilia B.

*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 (Europe) |
| Clinical trials | 171 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 B** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Hematuria — Very frequent (99-80%)
- Poor wound healing — Very frequent (99-80%)
- Intracranial hemorrhage — Very frequent (99-80%)
- Prolonged bleeding time — Very frequent (99-80%)
- Prolonged partial thromboplastin time — Very frequent (99-80%)
- Spontaneous, recurrent epistaxis — Very frequent (99-80%)
- Prolonged bleeding after surgery — Very frequent (99-80%)
- Joint hemorrhage — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0008732/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.Phe312Ser |
| Coding change (HGVS c.) | c.935T>C |
| MANE Select transcript | [NM_000132](https://www.ncbi.nlm.nih.gov/nuccore/NM_000132) |
| dbSNP | [rs137852405](https://www.ncbi.nlm.nih.gov/snp/rs137852405/) |
| Variant type | single nucleotide variant |
| Location | chrX:154969405-154969405 (GRCh38) |
| ClinVar | [VCV10196](https://www.ncbi.nlm.nih.gov/clinvar/variation/10196/) |

**All HGVS expressions:** `LRG_555:g.58319T>C`, `LRG_555t1:c.935T>C`, `NC_000023.10:g.154197680A>G`, `NC_000023.11:g.154969405A>G`, `NG_011403.2:g.58319T>C`, `NM_000132.4:c.935T>C`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.7711) — concordant with the pathogenic call
- REVEL 0.857 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -5.708 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL call this damaging; SaProt does not
- Conservation: phyloP 11.052, GERP 1.62, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 10%** most-pathogenic-predicted substitutions in F8 (of 13,814 modeled).
- CADD: **PHRED 25.0**. 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 0.74** across the covering region of the MANE Select transcript (154,931,512–154,969,409), spanning 37,897 bp. Chi-square p 2.6e-06. 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 **0.000112%** (nfe) · 1/895,416 in the highest group · 1/1,098,091 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, triplosensitivity 0 (0–3 scale). *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 **312** lies in a UniProt-annotated variant site (in hema; mild/moderate); a disulfide bond; a β-strand; the f5/8 type a 1 domain; the plastocyanin-like 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.Phe312Ser falls in the f5/8 type a 1 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/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-03-12.

**Submitter consensus:** conflicting (5 Pathogenic, 1 Likely pathogenic).

**Submission history:** 6 submissions (1991–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 1991-08-15 |
| Mayo Clinic Laboratories, Mayo Clinic | Pathogenic | criteria provided, single submitter | clinical testing | 2025-01-29 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Pathogenic | criteria provided, single submitter | clinical testing | 2025-03-12 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-10-25 |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-09-06 |
| NIHR Bioresource Rare Diseases, University of Cambridge | Pathogenic | criteria provided, single submitter | research | 2019-02-01 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Hereditary factor IX deficiency disease, Hereditary factor VIII deficiency disease, not provided, none provided, Christmas Disease, F9 DEFICIENCY, FACTOR IX DEFICIENCY, Hemophilia B, PLASMA THROMBOPLASTIN COMPONENT DEFICIENCY, HEMOPHILIA, CLASSIC.

## Similar variants {#similar}

Related F8 variant pages (same residue, condition, or type): [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), [F8 p.Arg2016Trp](/variant/f8-p-arg2016trp).

### 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 2026-07-14); 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 10196). 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.*