Is F8 p.Ala2108Val (c.6323C>T) pathogenic?

F8 p.Ala2108Val (c.6323C>T) is classified Uncertain significance in F8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-07-27). AlphaMissense: ambiguous (0.449); Very rare (popmax 0.000112%, nfe); Associated with Inborn genetic diseases.

What condition is associated with F8 p.Ala2108Val (c.6323C>T)?

F8 p.Ala2108Val (c.6323C>T) is associated with Inborn genetic diseases, hemophilia A (ClinVar).

How common is F8 p.Ala2108Val (c.6323C>T) in the general population?

F8 p.Ala2108Val (c.6323C>T) is very rare (popmax 0.000112%, nfe) (gnomAD).

What do computational predictors say about F8 p.Ala2108Val (c.6323C>T)?

AlphaMissense predicts ambiguous (score 0.449) — an in-silico prediction, not a clinical call.

F8 p.Ala2108Val

c.6323C>T · rs782094982 · VCV1330860

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.449 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000112%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.449	ambiguous
REVEL	0.736	pathogenic-leaning
SaProt	LLR -2.56	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 91 kb · p 1.5e-14 · regional, not allelic
Overall
CADD	25.3	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 0.000112% European (non-Finnish) · 1/894,178 alleles

Overall 0.000248% 3/1,208,546 alleles · very rare exomes 2/1,096,991 · genomes 1/111,555 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00421%	23,775
European (non-Finnish)grpmax	0.000112%	894,174

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.Ala2108Val
Coding: c.6323C>T
MANE Select: NM_000132
dbSNP: rs782094982
Type: single nucleotide variant
Location: chrX:154896183 (GRCh38)
Structure: AlphaFold pLDDT 61.20 · 29 PDB
Residue 2108: the f5/8 type c 1 domain; a β-strand

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hemophilia A

Similar variants

F8 p.Ala2108Pro Uncertain significance ★ ⚠ 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
F8 p.Arg1800His 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-ala2108val (accessed [today's date]).

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