Is F11 p.Cys339Phe (c.1016G>T) pathogenic?

F11 p.Cys339Phe (c.1016G>T) is classified Benign/Likely benign in F11 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.0925); Low-frequency (popmax 1.97%, afr); Associated with congenital factor XI deficiency.

What condition is associated with F11 p.Cys339Phe (c.1016G>T)?

F11 p.Cys339Phe (c.1016G>T) is associated with congenital factor XI deficiency (ClinVar).

How common is F11 p.Cys339Phe (c.1016G>T) in the general population?

F11 p.Cys339Phe (c.1016G>T) is low-frequency (popmax 1.97%, afr) (gnomAD).

How is Congenital factor XI deficiency inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about F11 p.Cys339Phe (c.1016G>T)?

AlphaMissense predicts likely benign (score 0.0925) — an in-silico prediction, not a clinical call.

F11 p.Cys339Phe

c.1016G>T · rs5967 · VCV348375

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0925 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.97%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital factor XI deficiency

Computational evidence

Protein change
AlphaMissense	0.0925	likely benign
REVEL	0.265	benign-leaning
SaProt	LLR -4.39	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.51	GERP -1.1
Overall
CADD	13.82	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 1.97% African / African-American · 1,476/75,040 alleles

Filtering AF 1.88% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.85%

Overall 0.11% 1,780/1,614,182 alleles · low-frequency exomes 940/1,461,876 · genomes 840/152,306 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.97%	51
Middle Eastern	0.379%	264
Admixed American	0.17%	588
Remaining individualsnot grpmax-eligible	0.152%	658
European (non-Finnish)	0.00695%	14,391
South Asian	0.0022%	45,541

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.Cys339Phe
Coding: c.1016G>T
MANE Select: NM_000128
dbSNP: rs5967
Type: single nucleotide variant
Location: chr4:186280373 (GRCh38)
Gene constraint: LOEUF 1.145 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.94 · 117 PDB
Residue 339: a turn; a disulfide bond; the apple 4 domain; a UniProt-annotated variant site (in)

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

Disease context

congenital factor XI deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Congenital factor XI deficiency (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: All ages
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

F11 p.Cys339Ter Conflicting classifications of pathogenicity ★ same residue
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.755+2T>C Pathogenic ★★ same condition
F11 c.865+2T>C Likely pathogenic ★★ same condition
F11 p.Ala109Thr 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-cys339phe (accessed [today's date]).

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