# NM_000131.5(F7):c.130G>A (p.Val44Ile)

https://sugi.bio/variant/f7-p-val44ile

## Summary

**F7 p.Val44Ile (c.130G>A)** is classified **Likely pathogenic** in F7 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-19). AlphaMissense: likely benign (0.1516); Very rare (popmax 0.000596%, nfe); Associated with congenital factor VII deficiency.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs368272420 · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.000596%, nfe)

## For patients & families {#patients}

This is a change in the F7 gene that is considered likely disease-causing, submitted by 1 submitter, 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.Val44Ile |
| Coding change (HGVS c.) | c.130G>A |
| MANE Select transcript | [NM_019616](https://www.ncbi.nlm.nih.gov/nuccore/NM_019616) (variant reported on NM_000131) |
| dbSNP | [rs368272420](https://www.ncbi.nlm.nih.gov/snp/rs368272420/) |
| Variant type | single nucleotide variant |
| Location | chr13:113106910-113106910 (GRCh38) |
| ClinVar | [VCV2506137](https://www.ncbi.nlm.nih.gov/clinvar/variation/2506137/) |

**All HGVS expressions:** `LRG_554:g.6120G>A`, `LRG_554t1:c.130G>A`, `NC_000013.10:g.113761224G>A`, `NC_000013.11:g.113106910G>A`, `NG_009262.1:g.6120G>A`, `NM_000131.5:c.130G>A`, `NM_001267554.2:c.64+1005G>A`, `NM_019616.4:c.64+1005G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1516) — ⚠ discordant with the pathogenic call
- REVEL 0.559 (indeterminate)
- SaProt LLR -8.174 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- SpliceAI predicts **donor loss** (Δ 0.50) — consistent with the pathogenic call
- Conservation: phyloP -0.318, GERP -0.45 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 8.156**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.50**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss at this position.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.000596%** (nfe) · FAF95 0.000248% · FAF99 0.000159% · 7/1,174,522 in the highest group · 7/1,602,372 alleles overall — very rare (popmax 0.000596%, 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}

**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}


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}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-05-19.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-05-19 |

## Associated conditions {#conditions}

[congenital factor VII deficiency](https://sugi.bio/atlas/disease/congenital-factor-vii-deficiency/).

**Reported phenotype names (ClinVar):** Congenital factor VII deficiency.

## Similar variants {#similar}

Related F7 variant pages (same residue, condition, or type): [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), [F7 c.-55C>T](/variant/f7-c-minus-55c-t), [F7 c.-61T>G](/variant/f7-c-minus-61t-g).

### 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 2506137). 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.*