# NM_019616.4(F7):c.142C>T (p.Pro48Ser)

https://sugi.bio/variant/f7-p-pro48ser

## Summary

**F7 p.Pro48Ser (c.142C>T)** is classified **Conflicting classifications of pathogenicity** in F7 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-11-21). AlphaMissense: likely benign (0.1073); Ultra-rare (popmax 0.0676%, nfe); Associated with Inborn genetic diseases.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs373376565 · 4 submitters · 2 linked conditions · AlphaMissense likely benign · ultra-rare (popmax 0.0676%, nfe)

## For patients & families {#patients}

This is a change in the F7 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 4 submitters, and is linked to Inborn genetic diseases.

*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 | [F7](https://sugi.bio/atlas/gene/F7/) |
| Protein change (HGVS p.) | p.Pro48Ser |
| Coding change (HGVS c.) | c.142C>T |
| MANE Select transcript | [NM_019616](https://www.ncbi.nlm.nih.gov/nuccore/NM_019616) |
| dbSNP | [rs373376565](https://www.ncbi.nlm.nih.gov/snp/rs373376565/) |
| Variant type | single nucleotide variant |
| Location | chr13:113110767-113110767 (GRCh38) |
| ClinVar | [VCV1703844](https://www.ncbi.nlm.nih.gov/clinvar/variation/1703844/) |

**All HGVS expressions:** `LRG_554:g.9977C>T`, `LRG_554t1:c.208C>T`, `LRG_554t2:c.142C>T`, `NC_000013.10:g.113765081C>T`, `NC_000013.11:g.113110767C>T`, `NG_009262.1:g.9977C>T`, `NM_000131.3:c.208C>T`, `NM_000131.5:c.208C>T`, `NM_001267554.2:c.65-3080C>T`, `NM_019616.4:c.142C>T`, `NR_051961.2:n.179C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.1073)
- REVEL 0.26 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -11.204 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense and REVEL do not
- Conservation: phyloP -3.731, GERP -3.76 — fast-evolving / accelerated position
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **P70S** vs ClinVar **P48S**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 2.085**. 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 **0.0676%** (nfe) · FAF95 0.0636% · FAF99 0.062% · 775/1,147,078 in the highest group · 842/1,549,952 alleles overall — ultra-rare (popmax 0.0676%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.0676% | 1,480 |
| East Asian | 0.0415% | 2,409 |
| Remaining individuals (not grpmax-eligible) | 0.03% | 3,333 |
| African / African-American | 0.0191% | 5,228 |
| Admixed American | 0.0157% | 6,386 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00699% | 14,315 |
| South Asian | 0.00595% | 16,810 |
| Finnish (not grpmax-eligible) | 0.00509% | 19,640 |

*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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2024-11-21.

**Submitter consensus:** conflicting (2 Uncertain significance, 1 not provided, 1 Likely benign).

**Submission history:** 4 submissions (2021–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology | Uncertain significance | criteria provided, single submitter | clinical testing |  |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-09-16 |
| GenomeConnect - Brain Gene Registry | not provided | no classification provided | phenotyping only |  |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-21 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/), [congenital factor VII deficiency](https://sugi.bio/atlas/disease/congenital-factor-vii-deficiency/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, Congenital factor VII deficiency, not specified, AllHighlyPenetrant.

## 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 1703844). 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.*