Is F9 p.Val331Ile (c.991G>A) pathogenic?

F9 p.Val331Ile (c.991G>A) is classified Conflicting classifications of pathogenicity in F9 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-09-23). AlphaMissense: likely benign (0.1335); Ultra-rare (popmax 0.0178%, eas); Associated with thrombophilia, X-linked, due to factor 9 defect.

What condition is associated with F9 p.Val331Ile (c.991G>A)?

F9 p.Val331Ile (c.991G>A) is associated with thrombophilia, X-linked, due to factor 9 defect, hemophilia B (ClinVar).

How common is F9 p.Val331Ile (c.991G>A) in the general population?

F9 p.Val331Ile (c.991G>A) is ultra-rare (popmax 0.0178%, eas) (gnomAD).

What do computational predictors say about F9 p.Val331Ile (c.991G>A)?

AlphaMissense predicts likely benign (score 0.1335) — an in-silico prediction, not a clinical call.

F9 p.Val331Ile

c.991G>A · rs776509489 · VCV1149534

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1335 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0178%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

thrombophilia, X-linked, due to factor 9 defect

Computational evidence

Protein change
AlphaMissense	0.1335	likely benign
REVEL	0.511	indeterminate
SaProt	LLR -8.11	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 8.6	GERP 5.1, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 25 kb · p 2.3e-14 · regional, not allelic
Overall
CADD	19.43	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 0.0178% East Asian · 6/33,766 alleles

Filtering AF 0.00766% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00527%

Overall 0.00124% 15/1,210,234 alleles · ultra-rare exomes 15/1,098,208 · genomes 0/112,026 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0178%	5,628
Finnishnot grpmax-eligible	0.00429%	23,306
European (non-Finnish)	0.000782%	127,904

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: F9
Protein: p.Val331Ile
Coding: c.991G>A
MANE Select: NM_000133
dbSNP: rs776509489
Type: single nucleotide variant
Location: chrX:139561676 (GRCh38)
Structure: AlphaFold pLDDT 80.45 · 57 PDB
Residue 331: a β-strand; the peptidase s1 domain

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

Disease context

thrombophilia, X-linked, due to factor 9 defect — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hemophilia B

Similar variants

F9 p.Val331Phe Uncertain significance ★ ⚠ same residue
F9 c.520+13A>G Pathogenic ★★★ same condition
F9 c.88+1G>A Pathogenic ★★★ same condition
F9 c.88+5G>T Likely pathogenic ★★★ same condition
F9 p.Ala279Thr Pathogenic ★★★ ⚠ same condition
F9 p.Ala337Pro Likely pathogenic ★★★ same condition
F9 p.Ala337Thr Pathogenic ★★★ ⚠ same condition
F9 p.Ala337Val 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/f9-p-val331ile (accessed [today's date]).

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