Is F8 p.Val104Ile (c.310G>A) pathogenic?

F8 p.Val104Ile (c.310G>A) is classified Uncertain significance in F8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-26). AlphaMissense: likely benign (0.0798); Very rare (popmax 0.000224%, nfe).

How common is F8 p.Val104Ile (c.310G>A) in the general population?

F8 p.Val104Ile (c.310G>A) is very rare (popmax 0.000224%, nfe) (gnomAD).

What do computational predictors say about F8 p.Val104Ile (c.310G>A)?

AlphaMissense predicts likely benign (score 0.0798) — an in-silico prediction, not a clinical call.

F8 p.Val104Ile

c.310G>A · VCV4812886

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0798 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000224%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.0798	likely benign
REVEL	0.319	indeterminate
SaProt	LLR -5.78	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP -1, phastCons 1
Regional constraint	o/e 0.56	unconstrained · MANE · 53 kb · p 1.5e-11 · regional, not allelic
Overall
CADD	15.19	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000224% European (non-Finnish) · 2/894,437 alleles

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

Overall 0.000165% 2/1,210,384 alleles · very rare exomes 2/1,097,049 · genomes 0/113,335 · joint denominator

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.Val104Ile
Coding: c.310G>A
MANE Select: NM_000132
Type: single nucleotide variant
Location: chrX:154997051 (GRCh38)
Structure: AlphaFold pLDDT 61.20 · 29 PDB
Residue 104: a β-strand; the f5/8 type a 1 domain; the plastocyanin-like 1 domain; a UniProt-annotated variant site (in hema; mild)

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

Similar variants

F8 p.Val104= Likely benign ★ same residue
F8 p.Val104Asp Pathogenic same residue
F8 c.6429+2T>A Pathogenic ★★★ same type
F8 p.Ala111Thr Likely pathogenic ★★★ same type
F8 p.Ala2220Pro Pathogenic ★★★ same type
F8 p.Ala415Asp Likely pathogenic ★★★ same type
F8 p.Ala415Val Pathogenic ★★★ ⚠ same type
F8 p.Arg1768His Pathogenic ★★★ ⚠ same type

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-val104ile (accessed [today's date]).

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