Is F9 p.Ser350Ala (c.1048T>G) pathogenic?

F9 p.Ser350Ala (c.1048T>G) is classified Conflicting classifications of pathogenicity in F9 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-11-06). AlphaMissense: likely benign (0.0851); Ultra-rare (popmax 0.08%, eas); Associated with hemophilia B.

What condition is associated with F9 p.Ser350Ala (c.1048T>G)?

F9 p.Ser350Ala (c.1048T>G) is associated with hemophilia B, thrombophilia, X-linked, due to factor 9 defect (ClinVar).

How common is F9 p.Ser350Ala (c.1048T>G) in the general population?

F9 p.Ser350Ala (c.1048T>G) is ultra-rare (popmax 0.08%, eas) (gnomAD).

How is Hemophilia B inherited?

Typically X-linked recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about F9 p.Ser350Ala (c.1048T>G)?

AlphaMissense predicts likely benign (score 0.0851) — an in-silico prediction, not a clinical call.

F9 p.Ser350Ala

c.1048T>G · rs147567879 · VCV1685803

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0851 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.08%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hemophilia B

ClinGen expert panel — Coagulation Factor Deficiency VCEP

Benign for hemophilia B. Applied ACMG criteria (verbatim):

BP4 BA1

Curation rationale (ClinGen, verbatim)

The c.1048T>G variant in F9 is a missense variant predicted to cause substitution of Serine by Alanine at amino acid 350 (p.Ser350Ala). This variant has been reported in 1 proband meeting phenotypic criteria for mild Hemophilia B. However, PS4_Supporting cannot be applied because more than 3 males in gnomAD v2.1.1 are reported with this variant, as per CFD VCEP specifications (PMID: 23492913). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0006494 (9/13858 alleles) in the East Asian population, which is higher than the ClinGen Coagulation Factor Deficiency VCEP threshold (>=0.0000556) for BA1, and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.291, which is below the threshold (<= 0.3) and the splice site predictor Splice AI indicated that the variant has no impact on splicing (score = 0,0,0,0), evidence that does not predict a damaging effect on F9 function (BP4). In summary, this variant meets the criteria to be classified as Benign for Hemophilia B based on the ACMG/AMP criteria applied, as specified by the ClinGen Coagulation Factor Deficiency VCEP (version 1.0.0, released 10/5/2023): BA1, BP4.

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.0851	likely benign
REVEL	0.291	indeterminate
SaProt	LLR -6.55	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 1.3	GERP 0.18, phastCons 0.96
Regional constraint	o/e 0.57	unconstrained · MANE · 25 kb · p 2.3e-14 · regional, not allelic
Overall
CADD	7.449	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 0.08% East Asian · 27/33,749 alleles

Filtering AF 0.0565% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0486%

Overall 0.00231% 28/1,210,442 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.08%	1,250
European (non-Finnish)	0.000112%	895,311

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.Ser350Ala
Coding: c.1048T>G
MANE Select: NM_000133
dbSNP: rs147567879
Type: single nucleotide variant
Location: chrX:139561733 (GRCh38)
Structure: AlphaFold pLDDT 80.45 · 57 PDB
Residue 350: a β-strand; the peptidase s1 domain

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

Disease context

hemophilia B — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: thrombophilia, X-linked, due to factor 9 defect

For Hemophilia B (Orphanet):

Inheritance: X-linked recessive
Onset: Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

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
F9 p.Arg191His 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-ser350ala (accessed [today's date]).

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