Is F9 p.Ile7Phe (c.19A>T) pathogenic?

F9 p.Ile7Phe (c.19A>T) is classified Benign in F9 (ClinVar, Expert panel, 11 submitters; last evaluated 2024-02-09). AlphaMissense: likely benign (0.0753); Rare (popmax 0.161%, nfe); Associated with hemophilia B.

What condition is associated with F9 p.Ile7Phe (c.19A>T)?

F9 p.Ile7Phe (c.19A>T) is associated with hemophilia B, thrombophilia, X-linked, due to factor 9 defect (ClinVar).

How common is F9 p.Ile7Phe (c.19A>T) in the general population?

F9 p.Ile7Phe (c.19A>T) is rare (popmax 0.161%, nfe) (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.Ile7Phe (c.19A>T)?

AlphaMissense predicts likely benign (score 0.0753) — an in-silico prediction, not a clinical call.

F9 p.Ile7Phe

c.19A>T · rs150190385 · VCV367997

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 11 submitters

AlphaMissense

likely benign

0.0753 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.161%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hemophilia B

ClinGen expert panel — Coagulation Factor Deficiency VCEP

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

BS2 BA1

Curation rationale (ClinGen, verbatim)

NM_000133.3:c.19A>T variant results in a missense change in the signal peptide. This variant is reported at a frequency of 0.001643 (152/92537 alleles with 57 hemizygotes) in the non-Finnish European population in gnomAD v2.1.1, meeting the BA1 cut-off of >= 0.0000556. At least 2 individuals with the variant and normal FIX levels from the literature and internal laboratory data are reported (PMID: 29296726) meeting the BS2 criterion. In summary, the variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: BA1, BS2.

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

Computational evidence

Protein change
AlphaMissense	0.0753	likely benign
REVEL	0.582	indeterminate
SaProt	LLR -7.04	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.6	GERP 2.9, phastCons 1
Regional constraint	o/e 1.17	unconstrained · MANE · 6,280 bp · p 0.32 · regional, not allelic
Overall
CADD	16.7	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 0.161% European (non-Finnish) · 1,437/894,566 alleles

Filtering AF 0.154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.151%

Overall 0.127% 1,538/1,209,789 alleles · rare exomes 1,438/1,097,226 · genomes 100/112,563 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.161%	623
Remaining individualsnot grpmax-eligible	0.0966%	1,035
Middle Eastern	0.0919%	1,088
Finnishnot grpmax-eligible	0.0449%	2,225
Admixed American	0.0437%	2,289
African / African-American	0.0174%	5,744

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.Ile7Phe
Coding: c.19A>T
MANE Select: NM_000133
dbSNP: rs150190385
Type: single nucleotide variant
Location: chrX:139530783 (GRCh38)
Structure: AlphaFold pLDDT 80.45 · 57 PDB
Residue 7: a UniProt-annotated variant site (in)

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-ile7phe (accessed [today's date]).

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