Is F9 p.Pro44Ser (c.130C>T) pathogenic?

F9 p.Pro44Ser (c.130C>T) is classified Likely benign in F9 (ClinVar, Expert panel, 3 submitters; last evaluated 2025-08-15). AlphaMissense: likely benign (0.1148); Very rare (popmax 0.00594%, eas); Associated with hemophilia B.

What condition is associated with F9 p.Pro44Ser (c.130C>T)?

F9 p.Pro44Ser (c.130C>T) is associated with hemophilia B, thrombophilia, X-linked, due to factor 9 defect (ClinVar).

How common is F9 p.Pro44Ser (c.130C>T) in the general population?

F9 p.Pro44Ser (c.130C>T) is very rare (popmax 0.00594%, 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.Pro44Ser (c.130C>T)?

AlphaMissense predicts likely benign (score 0.1148) — an in-silico prediction, not a clinical call.

F9 p.Pro44Ser

c.130C>T · rs776894974 · VCV1085717

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1148 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00594%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hemophilia B

ClinGen expert panel — Coagulation Factor Deficiency VCEP

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

BS1 BP4

Curation rationale (ClinGen, verbatim)

The c.130C>T; p.Pro44Ser variant has a Grpmax MAF of 0.00005825 in gnomAD v2.1.1 meeting BS1. The variant also has a REVEL score of 0.144 and Splice AI scores: Acceptor Loss: 0.00, Donor Loss: 0.05, Acceptor Gain: 0.00, Donor Gain: 0.00, meeting BP4. In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: BS1, BP4.

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

Computational evidence

Protein change
AlphaMissense	0.1148	likely benign
REVEL	0.144	moderately benign-leaning
SaProt	LLR -5.80	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 0.34	GERP 3.4
Regional constraint	o/e 0.57	unconstrained · MANE · 25 kb · p 2.3e-14 · regional, not allelic
Overall
CADD	14.45	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 0.00594% East Asian · 2/33,682 alleles

Filtering AF 0.000983% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000368%

Overall 0.000166% 2/1,207,787 alleles · very rare exomes 1/1,095,835 · genomes 1/111,952 · 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.Pro44Ser
Coding: c.130C>T
MANE Select: NM_000133
dbSNP: rs776894974
Type: single nucleotide variant
Location: chrX:139537051 (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 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-pro44ser (accessed [today's date]).

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