Is F8 p.Pro2319= (c.6957G>A) pathogenic?

F8 p.Pro2319= (c.6957G>A) is classified Likely benign in F8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-22). Ultra-rare (popmax 0.0423%, sas); Associated with hemophilia A.

What condition is associated with F8 p.Pro2319= (c.6957G>A)?

F8 p.Pro2319= (c.6957G>A) is associated with hemophilia A (ClinVar).

How common is F8 p.Pro2319= (c.6957G>A) in the general population?

F8 p.Pro2319= (c.6957G>A) is ultra-rare (popmax 0.0423%, sas) (gnomAD).

How is Hemophilia A inherited?

Typically X-linked recessive (Orphanet). A genetic counselor can assess individual risk for a family.

F8 p.Pro2319=

c.6957G>A · rs200902529 · VCV368115

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0423%, sas)

Conditions

hemophilia A

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -9.8	GERP -3.6
Overall
CADD	0.045	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0423% South Asian · 24/56,763 alleles

Filtering AF 0.0291% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0248%

Overall 0.00413% 50/1,209,738 alleles · ultra-rare exomes 47/1,097,642 · genomes 3/112,096 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0423%	2,365
Admixed American	0.0153%	6,548
Ashkenazi Jewishnot grpmax-eligible	0.0136%	7,343
Remaining individualsnot grpmax-eligible	0.0042%	23,801
East Asian	0.00296%	33,772
African / African-American	0.00175%	57,279
European (non-Finnish)	0.00134%	74,567

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: F8
Protein: p.Pro2319=
Coding: c.6957G>A
MANE Select: NM_000132
dbSNP: rs200902529
Type: single nucleotide variant
Location: chrX:154837696 (GRCh38)
Structure: AlphaFold pLDDT 61.20 · 29 PDB
Residue 2319: the f5/8 type c 2 domain; a UniProt-annotated variant site (in hema; mild/severe); a UniProt-annotated variant site (in hema; mild); a β-strand

Full F8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hemophilia A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hemophilia A (Orphanet):

Inheritance: X-linked recessive
Onset: Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

F8 p.Pro2319Leu Pathogenic ★★ ⚠ same residue
F8 p.Pro2319Ser Pathogenic/Likely pathogenic ★★ ⚠ same residue
F8 c.6429+2T>A Pathogenic ★★★ same condition
F8 p.Ala111Thr Likely pathogenic ★★★ same condition
F8 p.Ala2220Pro Pathogenic ★★★ same condition
F8 p.Ala415Asp Likely pathogenic ★★★ same condition
F8 p.Ala415Val Pathogenic ★★★ ⚠ same condition
F8 p.Arg1768His Pathogenic ★★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/f8-p-pro2319 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown