Is F9 p.Phe238Val (c.712T>G) pathogenic?

F9 p.Phe238Val (c.712T>G) is classified Benign in F9 (ClinVar, Expert panel, 2 submitters; last evaluated 2024-02-09). AlphaMissense: likely benign (0.2136); Ultra-rare (popmax 0.0267%, eas); Associated with hemophilia B.

What condition is associated with F9 p.Phe238Val (c.712T>G)?

F9 p.Phe238Val (c.712T>G) is associated with hemophilia B, thrombophilia, X-linked, due to factor 9 defect (ClinVar).

How common is F9 p.Phe238Val (c.712T>G) in the general population?

F9 p.Phe238Val (c.712T>G) is ultra-rare (popmax 0.0267%, 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.Phe238Val (c.712T>G)?

AlphaMissense predicts likely benign (score 0.2136) — an in-silico prediction, not a clinical call.

F9 p.Phe238Val

c.712T>G · rs143128467 · VCV1166447

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2136 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

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_000133.3:c.712T>G predicts a missense variant, Phe238Val, that is reported at a high MAF of 0.0008074 (12/14862 alleles with 4 hemizygotes) in the East Asian population of gnomAD v2.1.1, meeting the BA1 cut-off of >= 0.0000556. It is reported in the literature in at least one severe Hemophilia B patient who has an additional F9 variant. In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency VCEP for F9: BA1.

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

Computational evidence

Protein change
AlphaMissense	0.2136	likely benign
REVEL	0.547	indeterminate
SaProt	LLR -11.41	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>C here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.2	GERP 2.4, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 25 kb · p 2.3e-14 · regional, not allelic
Overall
CADD	15.66	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 0.0267% East Asian · 9/33,761 alleles

Filtering AF 0.0139% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0103%

Overall 0.00108% 13/1,206,745 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0267%	3,751
Remaining individualsnot grpmax-eligible	0.00211%	47,483
European (non-Finnish)	0.000336%	297,515

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.Phe238Val
Coding: c.712T>G
MANE Select: NM_000133
dbSNP: rs143128467
Type: single nucleotide variant
Location: chrX:139551253 (GRCh38)
Structure: AlphaFold pLDDT 80.45 · 57 PDB
Residue 238: a disulfide bond; the peptidase s1 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.Phe238= 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
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-phe238val (accessed [today's date]).

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