Is F8 p.Ala2220Pro (c.6658G>C) pathogenic?

F8 p.Ala2220Pro (c.6658G>C) is classified Pathogenic in F8 (ClinVar, Expert panel, 6 submitters; last evaluated 2025-08-15). AlphaMissense: likely pathogenic (0.6418); Very rare (popmax 0.000223%, nfe); Associated with hemophilia A.

What condition is associated with F8 p.Ala2220Pro (c.6658G>C)?

F8 p.Ala2220Pro (c.6658G>C) is associated with hemophilia A (ClinVar).

How common is F8 p.Ala2220Pro (c.6658G>C) in the general population?

F8 p.Ala2220Pro (c.6658G>C) is very rare (popmax 0.000223%, nfe) (gnomAD).

How is Hemophilia A inherited?

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

What do computational predictors say about F8 p.Ala2220Pro (c.6658G>C)?

AlphaMissense predicts likely pathogenic (score 0.6418) — an in-silico prediction, not a clinical call.

F8 p.Ala2220Pro

c.6658G>C · rs782548763 · VCV1029498

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.6418 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000223%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hemophilia A

ClinGen expert panel — Coagulation Factor Deficiency VCEP

Pathogenic for hemophilia A. Applied ACMG criteria (verbatim):

PP4_Moderate PS4_VeryStrong PM2_Supporting PP1_Moderate PP3

Curation rationale (ClinGen, verbatim)

The NM_000132.4(F8):c.6658G>C; p.Ala2220Pro is absent in males in gnomAD database v.2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.713, which is above the threshold of 0.6, evidence that correlates with impact to F8 function (PP3). This variant has been reported in at least 17 individuals with mild/moderate hemophilia A (PMID: 18034765 ; 20536985, 10910913, 29296726), meeting the PS4_Very Strong & PP4_Moderate criteria. This variant was found to co-segregate with the disease in multiple affected family members, with 7 meioses observed in one family (PP1_Moderate; PMID: 20536985). This variant has also been associated with incidence of inhibitor development to factor replacement products (PMID: 18034765). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the ClinGen Coagulation Factor Deficiency Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for F8 Version 1.0.0: PM2_Supporting, PP3, PS4_Very Strong, PP4_Moderate, PP1_Moderate.

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.6418	likely pathogenic ✓ concordant with ClinVar
REVEL	0.713	pathogenic-leaning
SaProt	LLR -10.98	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	GERP 0.51, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 91 kb · p 1.5e-14 · regional, not allelic
Overall
CADD	22.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000223% European (non-Finnish) · 2/895,258 alleles

Filtering AF 3.7e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.4e-05%

Overall 0.000248% 3/1,211,461 alleles · very rare exomes 3/1,097,891 · genomes 0/113,570 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0021%	47,631
European (non-Finnish)grpmax	0.000223%	447,630

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala2220Pro
Coding: c.6658G>C
MANE Select: NM_000132
dbSNP: rs782548763
Type: single nucleotide variant
Location: chrX:154861783 (GRCh38)
Structure: AlphaFold pLDDT 61.20 · 29 PDB
Residue 2220: the f5/8 type c 2 domain; 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

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F8 p.Ala415Asp Likely pathogenic ★★★ same condition
F8 p.Ala415Val Pathogenic ★★★ ⚠ same condition
F8 p.Arg1768His Pathogenic ★★★ ⚠ same condition
F8 p.Arg1800His Pathogenic ★★★ same condition
F8 p.Arg2016Trp Pathogenic ★★★ same condition
F8 p.Arg2326Ter 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-ala2220pro (accessed [today's date]).

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