Is CFC1 p.Pro217fs (c.649_655del) pathogenic?

CFC1 p.Pro217fs (c.649655del) is classified Uncertain significance in CFC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-01). Ultra-rare (popmax 0.0148%, amr).

How common is CFC1 p.Pro217fs (c.649_655del) in the general population?

CFC1 p.Pro217fs (c.649_655del) is ultra-rare (popmax 0.0148%, amr) (gnomAD).

CFC1 p.Pro217fs

c.649_655del · VCV3776528

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0148%, amr)

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 in the last exon (6 of 6) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -2.1
Region caveats
Repeat context	seg dup	· reads may not map uniquely · confidence, not pathogenicity

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0148% Admixed American · 3/20,316 alleles

Filtering AF 0.00401% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00208%

Overall 0.000715% 3/419,862 alleles · ultra-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: CFC1
Protein: p.Pro217fs
Coding: c.649_655del
MANE Select: NM_032545
Type: Deletion
Location: chr2:130592894 (GRCh38)
Gene constraint: LOEUF 0.586 · pLI 0.86 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.18

Full CFC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CFC1 p.Ala175fs Conflicting classifications of pathogenicity ★ same type
CFC1 p.Arg87fs Uncertain significance ★ same type
CFC1 p.Lys30fs Uncertain significance ★ 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/cfc1-p-pro217fs (accessed [today's date]).

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