Is F8 p.Leu173Phe (c.517C>T) pathogenic?

F8 p.Leu173Phe (c.517C>T) is classified Likely pathogenic in F8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-11). AlphaMissense: ambiguous (0.3712); Absent from gnomAD v4.1; Associated with F8-related disorder.

What condition is associated with F8 p.Leu173Phe (c.517C>T)?

F8 p.Leu173Phe (c.517C>T) is associated with F8-related disorder (ClinVar).

How common is F8 p.Leu173Phe (c.517C>T) in the general population?

F8 p.Leu173Phe (c.517C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about F8 p.Leu173Phe (c.517C>T)?

AlphaMissense predicts ambiguous (score 0.3712) — an in-silico prediction, not a clinical call.

F8 p.Leu173Phe

c.517C>T · rs2523977122 · VCV2631641

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3712 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

F8-related disorder

Computational evidence

Protein change
AlphaMissense	0.3712	ambiguous
REVEL	0.924	moderately pathogenic-leaning
SaProt	LLR -10.86	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 9.5	GERP 1.7, phastCons 1
Regional constraint	o/e 0.56	unconstrained · MANE · 53 kb · p 1.5e-11 · regional, not allelic
Overall
CADD	24.1	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: F8
Protein: p.Leu173Phe
Coding: c.517C>T
MANE Select: NM_000132
dbSNP: rs2523977122
Type: single nucleotide variant
Location: chrX:154993020 (GRCh38)
Structure: AlphaFold pLDDT 61.20 · 29 PDB
Residue 173: a disulfide bond; a β-strand; the f5/8 type a 1 domain; the plastocyanin-like 1 domain

Full F8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

F8-related disorder

Similar variants

F8 p.Arg1708Cys Pathogenic ★★ ⚠ same condition
F8 p.Arg1960Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
F8 p.Arg2169His Pathogenic ★★ ⚠ same condition
F8 p.Arg2326Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
F8 p.Arg602Gly Pathogenic/Likely pathogenic ★★ ⚠ same condition
F8 p.Arg717Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
F8 p.Glu291Lys Pathogenic ★★ ⚠ same condition
F8 p.Tyr1802Cys Pathogenic/Likely 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/f8-p-leu173phe (accessed [today's date]).

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