Is F9 p.Cys157= (c.471T>C) pathogenic?

F9 p.Cys157= (c.471T>C) is classified Uncertain significance in F9 (ClinVar, Expert panel, 2 submitters; last evaluated 2026-02-06). Absent from gnomAD v4.1; Associated with hemophilia B.

What condition is associated with F9 p.Cys157= (c.471T>C)?

F9 p.Cys157= (c.471T>C) is associated with hemophilia B, thrombophilia, X-linked, due to factor 9 defect (ClinVar).

How common is F9 p.Cys157= (c.471T>C) in the general population?

F9 p.Cys157= (c.471T>C) is absent from gnomAD v4.1 (gnomAD).

How is Hemophilia B inherited?

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

F9 p.Cys157=

c.471T>C · rs1603265493 · VCV798429

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 2 submitters

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

hemophilia B

ClinGen expert panel — Coagulation Factor Deficiency VCEP

Uncertain Significance for hemophilia B. Applied ACMG criteria (verbatim):

PM2_Supporting BP4

Curation rationale (ClinGen, verbatim)

The F9 c.471T>C (p.Cys157=) variant is absent from males in population databases (gnomAD v4.1.0). The Cys157= synonymous variant has an acceptor and donor gain SpliceAI score of 0.08 (<0.1 cutoff) based on meeting the BP4 code. The BP7 is not met due to its conservation scores. We are not aware of any cases of hemophilia B in the literature or in databases at this time. In summary, based on the evidence available at this time, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9 v2.0.0: PM2_Supporting, BP4.

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

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP 2, phastCons 1
Overall
CADD	6.918	PHRED · no single calibrated threshold — expert panels disagree

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.Cys157=
Coding: c.471T>C
MANE Select: NM_000133
dbSNP: rs1603265493
Type: single nucleotide variant
Location: chrX:139548442 (GRCh38)
Structure: AlphaFold pLDDT 80.45 · 57 PDB
Residue 157: the egf-like 2 domain; a disulfide bond

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.Cys157Tyr Pathogenic ★ same residue
F9 p.Cys157Ter Pathogenic ★ 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

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-cys157 (accessed [today's date]).

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