Is F9 p.Cys28Arg (c.82T>C) pathogenic?

F9 p.Cys28Arg (c.82T>C) is classified Pathogenic/Likely pathogenic in F9 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2021-03-24). AlphaMissense: likely benign (0.2472); Absent from gnomAD v4.1; Associated with F9-related disorders.

What condition is associated with F9 p.Cys28Arg (c.82T>C)?

F9 p.Cys28Arg (c.82T>C) is associated with F9-related disorders, thrombophilia, X-linked, due to factor 9 defect, hemophilia B (ClinVar).

How common is F9 p.Cys28Arg (c.82T>C) in the general population?

F9 p.Cys28Arg (c.82T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about F9 p.Cys28Arg (c.82T>C)?

AlphaMissense predicts likely benign (score 0.2472) — an in-silico prediction, not a clinical call.

F9 p.Cys28Arg

c.82T>C · rs387906481 · VCV10657

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2472 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

F9-related disorders

Computational evidence

Protein change
AlphaMissense	0.2472	likely benign ⚠ discordant with ClinVar
REVEL	0.621	indeterminate
SaProt	LLR -8.04	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.84 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.8	GERP 5.3, phastCons 1
Regional constraint	o/e 1.17	unconstrained · MANE · 6,280 bp · p 0.32 · regional, not allelic
Overall
CADD	18.47	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: F9
Protein: p.Cys28Arg
Coding: c.82T>C
MANE Select: NM_000133
dbSNP: rs387906481
Type: single nucleotide variant
Location: chrX:139530846 (GRCh38)
Structure: AlphaFold pLDDT 80.45 · 57 PDB
Residue 28: a UniProt-annotated variant site (in hemb; moderate; hb130); a UniProt-annotated variant site (in hemb; decreased protein abundance; decreased function in blood coagulation)

Full F9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

F9-related disorders

Also linked: thrombophilia, X-linked, due to factor 9 defect hemophilia B

Similar variants

F9 p.Cys28Tyr 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-cys28arg (accessed [today's date]).

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