Is F9 p.Leu20= (c.60A>G) pathogenic?

F9 p.Leu20= (c.60A>G) is classified Benign in F9 (ClinVar, Expert panel, 5 submitters; last evaluated 2024-02-09). Very rare (popmax 0.000224%, nfe); Associated with hemophilia B.

What condition is associated with F9 p.Leu20= (c.60A>G)?

F9 p.Leu20= (c.60A>G) is associated with hemophilia B, thrombophilia, X-linked, due to factor 9 defect (ClinVar).

How common is F9 p.Leu20= (c.60A>G) in the general population?

F9 p.Leu20= (c.60A>G) is very rare (popmax 0.000224%, nfe) (gnomAD).

How is Hemophilia B inherited?

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

F9 p.Leu20=

c.60A>G · rs762082146 · VCV701352

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000224%, nfe)

Conditions

hemophilia B

ClinGen expert panel — Coagulation Factor Deficiency VCEP

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

BP7 BP4 BA1

Curation rationale (ClinGen, verbatim)

The NM_000133.4(F9):c.60A>G (p.Leu20=) synonymous variant is reported at an MAF of 0.0009351 (7/7486 alleles) in the Ashkenazi Jewish population in gnomAD v2.1.1 with 4 hemizygotes, meeting BA1 criteria of MAF > 0.0000556. SpliceAI predicts no splicing impact with a score of 0.0, meeting BP4 and BP7 criteria (<0.01). In summary, based on the evidence available at this time, the clinical significance of this variant is benign. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: BA1, BP4 and BP7.

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 0.11	GERP -4.7, phastCons 0.39
Overall
CADD	3.619	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000224% European (non-Finnish) · 2/892,877 alleles

Filtering AF 3.7e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.4e-05%

Overall 0.00248% 30/1,207,862 alleles · very rare exomes 29/1,095,400 · genomes 1/112,462 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.109%	917
Remaining individualsnot grpmax-eligible	0.00842%	11,875
European (non-Finnish)grpmax	0.000224%	446,439

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Leu20=
Coding: c.60A>G
MANE Select: NM_000133
dbSNP: rs762082146
Type: single nucleotide variant
Location: chrX:139530824 (GRCh38)
Structure: AlphaFold pLDDT 80.45 · 57 PDB
Residue 20: a UniProt-annotated variant site (in hemb; uncertain significance; decreased protein abundance; decreased function in blood coagulation)

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.Leu20Ser 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
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-leu20 (accessed [today's date]).

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