Is F12 p.Asp557fs (c.1668del) pathogenic?

F12 p.Asp557fs (c.1668del) is classified Uncertain significance in F12 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-14). Very rare (popmax 0.000763%, nfe).

How common is F12 p.Asp557fs (c.1668del) in the general population?

F12 p.Asp557fs (c.1668del) is very rare (popmax 0.000763%, nfe) (gnomAD).

F12 p.Asp557fs

c.1668del · rs1561639482 · VCV1036898

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000763%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon within the last 50 nt of the penultimate exon (13 of 14, 12 nt from its 3' end) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 5.9	GERP 2.3, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000763% European (non-Finnish) · 9/1,179,348 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000617% 9/1,459,332 alleles · very rare

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: F12
Protein: p.Asp557fs
Coding: c.1668del
MANE Select: NM_000505
dbSNP: rs1561639482
Type: Deletion
Location: chr5:177402562 (GRCh38)
Gene constraint: LOEUF 1.286 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.47 · 17 PDB
Residue 557: a β-strand; a disulfide bond; the peptidase s1 domain

Full F12 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

F12 c.971_1018+24del Pathogenic/Likely pathogenic ★★ same type
F12 p.Gly506fs Likely pathogenic ★★ same type
F12 c.1018+19del Benign/Likely benign ★★ same type
F12 p.Val524fs Pathogenic ★ same type
F12 p.Glu154_Ala157del Uncertain significance ★ same type
F12 p.Pro566fs Uncertain significance ★ same type
F12 c.1251-5del Likely benign same type

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/f12-p-asp557fs (accessed [today's date]).

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