# NM_019616.4(F7):c.845C>T (p.Ala282Val)

https://sugi.bio/variant/f7-p-ala282val

## Summary

**F7 p.Ala282Val (c.845C>T)** is classified **Pathogenic/Likely pathogenic** in F7 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2025-05-22). AlphaMissense: likely benign (0.1799); Rare (popmax 0.165%, mid); Associated with congenital factor VII deficiency.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs121964931 · 10 submitters · 3 linked conditions · AlphaMissense likely benign · rare (popmax 0.165%, mid)

## For patients & families {#patients}

This is a change in the F7 gene that is considered likely disease-causing, submitted by 10 submitters, and is linked to congenital factor VII deficiency.

*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) | Autosomal dominant, Autosomal recessive |
| Age of onset (of this condition) | All ages |
| Prevalence | 1-9 / 1 000 000 (Europe) |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | F7 is a diagnostic-grade gene on 3 Genomics England panels |

**Commonly reported features of Congenital factor VII deficiency** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Intracranial hemorrhage — Very frequent (99-80%)
- Gastrointestinal hemorrhage — Very frequent (99-80%)
- Menorrhagia — Frequent (79-30%)
- Gingival bleeding — Frequent (79-30%)
- Epistaxis — Frequent (79-30%)
- Bruising susceptibility — Frequent (79-30%)
- Prolonged bleeding after surgery — Frequent (79-30%)
- Joint hemorrhage — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0002238/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [F7](https://sugi.bio/atlas/gene/F7/) |
| Protein change (HGVS p.) | p.Ala282Val |
| Coding change (HGVS c.) | c.845C>T |
| MANE Select transcript | [NM_019616](https://www.ncbi.nlm.nih.gov/nuccore/NM_019616) |
| dbSNP | [rs121964931](https://www.ncbi.nlm.nih.gov/snp/rs121964931/) |
| Variant type | single nucleotide variant |
| Location | chr13:113118518-113118518 (GRCh38) |
| ClinVar | [VCV627403](https://www.ncbi.nlm.nih.gov/clinvar/variation/627403/) |

**All HGVS expressions:** `LRG_548:g.720C>T`, `LRG_554:g.17728C>T`, `LRG_554t1:c.911C>T`, `LRG_554t2:c.845C>T`, `NC_000013.10:g.113772832C>T`, `NC_000013.11:g.113118518C>T`, `NG_009258.1:g.720C>T`, `NG_009262.1:g.17728C>T`, `NM_000131.5:c.911C>T`, `NM_001267554.2:c.659C>T`, `NM_019616.4:c.845C>T`, `NR_051961.2:n.929C>T`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — AlphaMissense predicts likely-benign.

- AlphaMissense **likely benign** (0.1799) — ⚠ discordant with the pathogenic call
- REVEL 0.698 (pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -10.622 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** REVEL and SaProt call this damaging; AlphaMissense does not
- Conservation: phyloP 2.108, GERP -0.474, phastCons 0.976 — highly conserved (differs from AlphaMissense)
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **A304V** vs ClinVar **A282V**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 20.6**. 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 0.95** across the covering region of the MANE Select transcript (113,105,842–113,119,005), spanning 13,163 bp. Chi-square p 0.22. 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 **0.165%** (mid) · FAF95 0.0895% · FAF99 0.0681% · 10/6,060 in the highest group · 84/1,611,680 alleles overall — rare (popmax 0.165%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.165% | 606 |
| Admixed American | 0.0533% | 1,876 |
| Remaining individuals (not grpmax-eligible) | 0.0192% | 5,206 |
| South Asian | 0.00769% | 13,012 |
| African / African-American | 0.00533% | 18,764 |
| European (non-Finnish) | 0.00161% | 62,100 |

*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}

**F7** population constraint: LOEUF 1.113, pLI 1.1139e-11, missense-Z 0.3692; ClinGen dosage — haploinsufficiency 30, triplosensitivity Not yet evaluated (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):

- **factor VII deficiency** — Definitive (AR)

## Protein context {#protein}

Residue **282** lies in a β-strand; a disulfide bond; the peptidase s1 domain.

AlphaFold model confidence (whole protein): pLDDT 82.64, 49% of residues very-high.

**114 experimental structure(s)** (PDB): [1BF9](https://www.rcsb.org/structure/1BF9), [1CVW](https://www.rcsb.org/structure/1CVW), [1DAN](https://www.rcsb.org/structure/1DAN), [1DVA](https://www.rcsb.org/structure/1DVA), [1F7E](https://www.rcsb.org/structure/1F7E), [1F7M](https://www.rcsb.org/structure/1F7M) — incl. mutant structure 1FAK.

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

*Describes the biological roles of F7 (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.*


### Pathways affected {#pathways}

F7 participates in **7 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Gamma-carboxylation of protein precursors](https://reactome.org/content/detail/R-HSA-159740) | curated |
| [Initiation of coagulation cascade](https://reactome.org/content/detail/R-HSA-9769735) | curated |
| [Regulation of clotting cascade](https://reactome.org/content/detail/R-HSA-9769739) | curated |
| [Removal of aminoterminal propeptides from gamma-carboxylated proteins](https://reactome.org/content/detail/R-HSA-159782) | curated |
| [Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus](https://reactome.org/content/detail/R-HSA-159763) | curated |
| [None](https://reactome.org/content/detail/R-HSA-140834) | other |
| [BMAL1:CLOCK,NPAS2 activates circadian expression](https://reactome.org/content/detail/R-HSA-1368108) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Biological process:** positive regulation of leukocyte chemotaxis, blood coagulation, positive regulation of platelet-derived growth factor receptor signaling pathway, protein processing, positive regulation of TOR signaling, positive regulation of positive chemotaxis.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-05-22.

**Submitter consensus:** conflicting (8 Pathogenic, 2 Likely pathogenic).

**Submission history:** 10 submissions (1996–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 1996-09-01 |
| ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology | Likely pathogenic | criteria provided, single submitter | clinical testing |  |
| Fulgent Genetics, Fulgent Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2022-04-28 |
| 3billion | Pathogenic | criteria provided, single submitter | clinical testing | 2023-02-23 |
| Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS) | Pathogenic | no assertion criteria provided | clinical testing | 2023-04-01 |
| NIHR Bioresource Rare Diseases, University of Cambridge | Likely pathogenic | criteria provided, single submitter | research | 2019-02-01 |
| Mayo Clinic Laboratories, Mayo Clinic | Pathogenic | criteria provided, single submitter | clinical testing | 2024-10-14 |
| PreventionGenetics, part of Exact Sciences | Pathogenic | no assertion criteria provided | clinical testing | 2024-03-14 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2025-05-22 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-03-15 |

## Associated conditions {#conditions}

[congenital factor VII deficiency](https://sugi.bio/atlas/disease/congenital-factor-vii-deficiency/), [factor VII deficiency](https://sugi.bio/atlas/disease/factor-vii-deficiency/), [myocardial infarction, susceptibility to](https://sugi.bio/atlas/disease/myocardial-infarction-susceptibility-to/).

**Reported phenotype names (ClinVar):** Congenital factor VII deficiency, Factor VII deficiency, not provided, Myocardial infarction, susceptibility to, F7-related disorder, F7-related disorders, F7-related condition, Factor 7 deficiency, F7 DEFICIENCY, HYPOPROCONVERTINEMIA.

## Similar variants {#similar}

Related F7 variant pages (same residue, condition, or type): [F7 p.Ala282Thr](/variant/f7-p-ala282thr), [F7 p.Ala282=](/variant/f7-p-ala282), [F7 c.225+1G>C](/variant/f7-c-225-plus-1g-c), [F7 c.364+1G>A](/variant/f7-c-364-plus-1g-a), [F7 c.505+78G>A](/variant/f7-c-505-plus-78g-a), [F7 c.615+1G>T](/variant/f7-c-615-plus-1g-t), [F7 c.739+1G>A](/variant/f7-c-739-plus-1g-a), [F7 c.-30A>C](/variant/f7-c-minus-30a-c).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 627403). 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.*