Is F8 p.Arg1985Gln (c.5954G>A) pathogenic?

F8 p.Arg1985Gln (c.5954G>A) is classified Pathogenic/Likely pathogenic in F8 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-08-18). AlphaMissense: likely benign (0.1209); Very rare (popmax 0.00123%, nfe); Associated with hemophilia B.

What condition is associated with F8 p.Arg1985Gln (c.5954G>A)?

F8 p.Arg1985Gln (c.5954G>A) is associated with hemophilia B, hemophilia A (ClinVar).

How common is F8 p.Arg1985Gln (c.5954G>A) in the general population?

F8 p.Arg1985Gln (c.5954G>A) is very rare (popmax 0.00123%, 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 F8 p.Arg1985Gln (c.5954G>A)?

AlphaMissense predicts likely benign (score 0.1209) — an in-silico prediction, not a clinical call.

F8 p.Arg1985Gln

c.5954G>A · rs1490417405 · VCV618098

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.1209 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00123%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hemophilia B

Computational evidence

Protein change
AlphaMissense	0.1209	likely benign ⚠ discordant with ClinVar
REVEL	0.687	pathogenic-leaning
SaProt	LLR -4.24	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 91 kb · p 1.5e-14 · regional, not allelic
Overall
CADD	24.8	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 0.00123% European (non-Finnish) · 11/893,507 alleles

Filtering AF 0.000661% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000483%

Overall 0.000994% 12/1,207,243 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0021%	47,507
European (non-Finnish)grpmax	0.00123%	81,228

Remaining individuals 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: F8
Protein: p.Arg1985Gln
Coding: c.5954G>A
MANE Select: NM_000132
dbSNP: rs1490417405
Type: single nucleotide variant
Location: chrX:154903950 (GRCh38)
Structure: AlphaFold pLDDT 61.20 · 29 PDB
Residue 1985: the f5/8 type a 3 domain; the plastocyanin-like 6 domain; a UniProt-annotated variant site (in hema; mild); a β-strand

Full F8 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: hemophilia A

For Hemophilia B (Orphanet):

Inheritance: X-linked recessive
Onset: Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

F8 p.Arg1985Ter Pathogenic ★★ same residue
F8 p.Arg1985Gly Likely pathogenic ★ same residue
F8 p.Arg1985Pro Likely pathogenic ★ ⚠ same residue
F8 c.6429+2T>A Pathogenic ★★★ same condition
F8 p.Ala111Thr Likely pathogenic ★★★ same condition
F8 p.Ala2220Pro Pathogenic ★★★ same condition
F8 p.Ala415Asp Likely pathogenic ★★★ same condition
F8 p.Ala415Val 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-arg1985gln (accessed [today's date]).

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