Is F8 p.Val64Met (c.190G>A) pathogenic?

F8 p.Val64Met (c.190G>A) is classified Uncertain significance in F8 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-06-18). AlphaMissense: likely benign (0.0683); Ultra-rare (popmax 0.0679%, amr).

How common is F8 p.Val64Met (c.190G>A) in the general population?

F8 p.Val64Met (c.190G>A) is ultra-rare (popmax 0.0679%, amr) (gnomAD).

What do computational predictors say about F8 p.Val64Met (c.190G>A)?

AlphaMissense predicts likely benign (score 0.0683) — an in-silico prediction, not a clinical call.

F8 p.Val64Met

c.190G>A · rs187738612 · VCV1330470

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0683 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0679%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0683	likely benign
REVEL	0.511	indeterminate
SaProt	LLR -8.28	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.6	GERP -2.9
Regional constraint	o/e 0.56	unconstrained · MANE · 53 kb · p 1.5e-11 · regional, not allelic
Overall
CADD	0.211	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 0.0679% Admixed American · 31/45,658 alleles

Filtering AF 0.0491% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0427%

Overall 0.00638% 77/1,206,010 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0679%	1,473
Remaining individualsnot grpmax-eligible	0.0169%	5,926
East Asian	0.0119%	8,403
African / African-American	0.00701%	14,257
South Asian	0.00353%	28,352
European (non-Finnish)	0.00314%	31,872

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.Val64Met
Coding: c.190G>A
MANE Select: NM_000132
dbSNP: rs187738612
Type: single nucleotide variant
Location: chrX:154999554 (GRCh38)
Structure: AlphaFold pLDDT 61.20 · 29 PDB
Residue 64: the f5/8 type a 1 domain; the plastocyanin-like 1 domain

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

Similar variants

F8 p.Val64Gly Uncertain significance ★ ⚠ 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
F8 p.Arg1800His 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-val64met (accessed [today's date]).

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