Is F9 p.Arg3Cys (c.7C>T) pathogenic?

F9 p.Arg3Cys (c.7C>T) is classified Benign in F9 (ClinVar, Expert panel, 3 submitters; last evaluated 2026-02-06). AlphaMissense: likely benign (0.0809); Ultra-rare (popmax 0.0415%, eas); Associated with hemophilia B.

What condition is associated with F9 p.Arg3Cys (c.7C>T)?

F9 p.Arg3Cys (c.7C>T) is associated with hemophilia B, thrombophilia, X-linked, due to factor 9 defect (ClinVar).

How common is F9 p.Arg3Cys (c.7C>T) in the general population?

F9 p.Arg3Cys (c.7C>T) is ultra-rare (popmax 0.0415%, 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.Arg3Cys (c.7C>T)?

AlphaMissense predicts likely benign (score 0.0809) — an in-silico prediction, not a clinical call.

F9 p.Arg3Cys

c.7C>T · rs766259893 · VCV765903

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0809 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0415%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hemophilia B

ClinGen expert panel — Coagulation Factor Deficiency VCEP

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

BA1

Curation rationale (ClinGen, verbatim)

The NM_000133.4(F9):c.7C>T; p.Arg3Cys variant is a missense variant in F9 that has a MAF of 0.0006498 (9/13851 alleles) in the East Asian population in gnomAD v2.1.1 with 3 hemizygotes, meeting BA1 criteria of MAF > 0.0000556. In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel v1.0 rule specifications for F9: BA1.

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

Computational evidence

Protein change
AlphaMissense	0.0809	likely benign
REVEL	0.157	moderately benign-leaning
SaProt	LLR -7.46	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.69	GERP -2.5
Regional constraint	o/e 1.17	unconstrained · MANE · 6,280 bp · p 0.32 · regional, not allelic
Overall
CADD	6.297	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 0.0415% East Asian · 14/33,757 alleles

Filtering AF 0.025% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0201%

Overall 0.0024% 29/1,207,866 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0415%	2,411
Admixed American	0.00874%	11,442
Remaining individualsnot grpmax-eligible	0.00421%	23,766
European (non-Finnish)	0.00101%	99,215

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.Arg3Cys
Coding: c.7C>T
MANE Select: NM_000133
dbSNP: rs766259893
Type: single nucleotide variant
Location: chrX:139530771 (GRCh38)
Structure: AlphaFold pLDDT 80.45 · 57 PDB

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.Arg3His Benign ★★★ same residue
F9 p.Arg3= Likely benign ★ same residue
F9 p.Arg3Ser Likely benign ★ 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

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-arg3cys (accessed [today's date]).

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