Is F8 p.Arg2178His (c.6533G>A) pathogenic?

F8 p.Arg2178His (c.6533G>A) is classified Pathogenic/Likely pathogenic in F8 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-02-26). AlphaMissense: likely benign (0.3021); Very rare (popmax 0.00173%, afr); Associated with hemophilia B.

What condition is associated with F8 p.Arg2178His (c.6533G>A)?

F8 p.Arg2178His (c.6533G>A) is associated with hemophilia B, hemophilia A (ClinVar).

How common is F8 p.Arg2178His (c.6533G>A) in the general population?

F8 p.Arg2178His (c.6533G>A) is very rare (popmax 0.00173%, afr) (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.Arg2178His (c.6533G>A)?

AlphaMissense predicts likely benign (score 0.3021) — an in-silico prediction, not a clinical call.

F8 p.Arg2178His

c.6533G>A · rs137852465 · VCV10319

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.3021 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00173%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hemophilia B

Computational evidence

Protein change
AlphaMissense	0.3021	likely benign ⚠ discordant with ClinVar
REVEL	0.82	moderately pathogenic-leaning
SaProt	LLR -3.21	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 5.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 91 kb · p 1.5e-14 · regional, not allelic
Overall
CADD	26.1	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

Grpmax group 0.00173% African / African-American · 1/57,672 alleles

Filtering AF 0.000473% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000343%

Overall 0.000991% 12/1,210,698 alleles · very rare exomes 12/1,097,292 · genomes 0/113,406 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00454%	22,033
Remaining individualsnot grpmax-eligible	0.0021%	47,603
African / African-Americangrpmax	0.00173%	57,672
European (non-Finnish)	0.00101%	99,410

Ashkenazi Jewish 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.Arg2178His
Coding: c.6533G>A
MANE Select: NM_000132
dbSNP: rs137852465
Type: single nucleotide variant
Location: chrX:154863124 (GRCh38)
Structure: AlphaFold pLDDT 61.20 · 29 PDB
Residue 2178: the f5/8 type c 1 domain; a UniProt-annotated variant site (in hema; mild/moderate); 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.Arg2178Cys Pathogenic/Likely pathogenic ★★ ⚠ same residue
F8 p.Arg2178Leu 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
F8 p.Arg1768His 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-arg2178his (accessed [today's date]).

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