Is F9 p.Val228Ala (c.683T>C) pathogenic?

F9 p.Val228Ala (c.683T>C) is classified Uncertain significance in F9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-14). AlphaMissense: ambiguous (0.3637); Absent from gnomAD v4.1.

How common is F9 p.Val228Ala (c.683T>C) in the general population?

F9 p.Val228Ala (c.683T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about F9 p.Val228Ala (c.683T>C)?

AlphaMissense predicts ambiguous (score 0.3637) — an in-silico prediction, not a clinical call.

F9 p.Val228Ala

c.683T>C · VCV4536709

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3637 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3637	ambiguous
REVEL	0.935	strongly pathogenic-leaning
SaProt	LLR -11.15	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 4.9, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 25 kb · p 2.3e-14 · regional, not allelic
Overall
CADD	24.6	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: F9
Protein: p.Val228Ala
Coding: c.683T>C
MANE Select: NM_000133
Type: single nucleotide variant
Location: chrX:139551224 (GRCh38)
Structure: AlphaFold pLDDT 80.45 · 57 PDB
Residue 228: a UniProt-annotated variant site (in hemb; severe; kashihara); a UniProt-annotated variant site (in hemb; mild; cardiff-2); a disulfide bond; the peptidase s1 domain

Full F9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

F9 p.Val228Gly Likely pathogenic ★ same residue
F9 p.Val228Phe Pathogenic ★ same residue
F9 p.Val228Ile Uncertain significance ★ ⚠ same residue
F9 p.Val228Leu Pathogenic same residue
F9 c.520+13A>G Pathogenic ★★★ same type
F9 c.88+1G>A Pathogenic ★★★ same type
F9 c.88+5G>T Likely pathogenic ★★★ same type
F9 p.Ala279Thr 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/f9-p-val228ala (accessed [today's date]).

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