Is F9 p.Phe55Ile (c.163T>A) pathogenic?

F9 p.Phe55Ile (c.163T>A) is classified Pathogenic/Likely pathogenic in F9 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-04-22). AlphaMissense: likely benign (0.1328); Very rare (popmax 0.000895%, nfe); Associated with hemophilia B.

What condition is associated with F9 p.Phe55Ile (c.163T>A)?

F9 p.Phe55Ile (c.163T>A) is associated with hemophilia B, thrombophilia, X-linked, due to factor 9 defect (ClinVar).

How common is F9 p.Phe55Ile (c.163T>A) in the general population?

F9 p.Phe55Ile (c.163T>A) is very rare (popmax 0.000895%, nfe) (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.Phe55Ile (c.163T>A)?

AlphaMissense predicts likely benign (score 0.1328) — an in-silico prediction, not a clinical call.

F9 p.Phe55Ile

c.163T>A · rs759987427 · VCV1069182

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1328 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000895%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hemophilia B

Computational evidence

Protein change
AlphaMissense	0.1328	likely benign ⚠ discordant with ClinVar
REVEL	0.653	pathogenic-leaning
SaProt	LLR -4.84	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.4	GERP 0.071, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 25 kb · p 2.3e-14 · regional, not allelic
Overall
CADD	16.57	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 0.000895% European (non-Finnish) · 8/894,128 alleles

Filtering AF 0.000385% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000278%

Overall 0.000662% 8/1,208,545 alleles · very rare exomes 6/1,096,846 · genomes 2/111,699 · 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: F9
Protein: p.Phe55Ile
Coding: c.163T>A
MANE Select: NM_000133
dbSNP: rs759987427
Type: single nucleotide variant
Location: chrX:139537084 (GRCh38)
Structure: AlphaFold pLDDT 80.45 · 57 PDB
Residue 55: a UniProt-annotated variant site (in hemb); the gla 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 p.Phe55Leu 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-phe55ile (accessed [today's date]).

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