Is F9 p.Pro101Ala (c.301C>G) pathogenic?

F9 p.Pro101Ala (c.301C>G) is classified Pathogenic in F9 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-10-01). AlphaMissense: ambiguous (0.4289); Very rare (popmax 0.00353%, afr); Associated with hemophilia B.

What condition is associated with F9 p.Pro101Ala (c.301C>G)?

F9 p.Pro101Ala (c.301C>G) is associated with hemophilia B, thrombophilia, X-linked, due to factor 9 defect (ClinVar).

How common is F9 p.Pro101Ala (c.301C>G) in the general population?

F9 p.Pro101Ala (c.301C>G) is very rare (popmax 0.00353%, afr) (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.Pro101Ala (c.301C>G)?

AlphaMissense predicts ambiguous (score 0.4289) — an in-silico prediction, not a clinical call.

F9 p.Pro101Ala

c.301C>G · rs137852232 · VCV10578

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.4289 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00353%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

hemophilia B

Computational evidence

Protein change
AlphaMissense	0.4289	ambiguous
REVEL	0.936	strongly pathogenic-leaning
SaProt	LLR -13.39	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 5.3, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 25 kb · p 2.3e-14 · regional, not allelic
Overall
CADD	25.1	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 0.00353% African / African-American · 2/56,711 alleles

Filtering AF 0.000585% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000219%

Overall 0.000167% 2/1,195,966 alleles · very rare exomes 0/1,084,417 · genomes 2/111,549 · 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.Pro101Ala
Coding: c.301C>G
MANE Select: NM_000133
dbSNP: rs137852232
Type: single nucleotide variant
Location: chrX:139541099 (GRCh38)
Structure: AlphaFold pLDDT 80.45 · 57 PDB
Residue 101: a UniProt-annotated variant site (in hemb); the egf-like 1; calcium-binding 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.Pro101Gln Likely pathogenic ★ same residue
F9 p.Pro101= 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
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-pro101ala (accessed [today's date]).

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