Is F11 p.Arg228Ter (c.682C>T) pathogenic?

F11 p.Arg228Ter (c.682C>T) is classified Pathogenic/Likely pathogenic in F11 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-04-17). Very rare (popmax 0.00333%, amr); Associated with Plasma factor XI deficiency.

What condition is associated with F11 p.Arg228Ter (c.682C>T)?

F11 p.Arg228Ter (c.682C>T) is associated with Plasma factor XI deficiency, congenital factor XI deficiency (ClinVar).

How common is F11 p.Arg228Ter (c.682C>T) in the general population?

F11 p.Arg228Ter (c.682C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

F11 p.Arg228Ter

c.682C>T · rs752907087 · VCV188795

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Conditions

Plasma factor XI deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 7 of 15
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.8	GERP -1.7
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/59,988 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000342% 5/1,461,888 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	29,994
South Asian	0.0022%	45,542
European (non-Finnish)	8.47e-05%	1,180,011

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: F11
Protein: p.Arg228Ter
Coding: c.682C>T
MANE Select: NM_000128
dbSNP: rs752907087
Type: single nucleotide variant
Location: chr4:186276317 (GRCh38)
Gene constraint: LOEUF 1.145 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.94 · 117 PDB
Residue 228: an α-helix; a disulfide bond; the apple 3 domain; a UniProt-annotated variant site (in fa11d)

Full F11 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Plasma factor XI deficiency

Also linked: congenital factor XI deficiency

Similar variants

F11 p.Arg228Gln Uncertain significance ★ ⚠ same residue
F11 c.1136-1G>C Likely pathogenic ★★ same condition
F11 c.1481-1G>T Likely pathogenic ★★ same condition
F11 c.1716+1G>A Pathogenic ★★ same condition
F11 c.325+1G>A Pathogenic ★★ same condition
F11 c.326-1G>A Pathogenic ★★ same condition
F11 c.595+3A>G Pathogenic/Likely pathogenic ★★ same condition
F11 c.755+2T>C 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/f11-p-arg228ter (accessed [today's date]).

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