Is CFAP221 p.Lys74fs (c.222del) pathogenic?

CFAP221 p.Lys74fs (c.222del) is classified Likely pathogenic in CFAP221 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-06-16). Very rare (popmax 0.00735%, eas); Associated with Young syndrome.

What condition is associated with CFAP221 p.Lys74fs (c.222del)?

CFAP221 p.Lys74fs (c.222del) is associated with Young syndrome (ClinVar).

How common is CFAP221 p.Lys74fs (c.222del) in the general population?

CFAP221 p.Lys74fs (c.222del) is very rare (popmax 0.00735%, eas) (gnomAD).

How is Young syndrome inherited?

Typically Unknown (Orphanet). A genetic counselor can assess individual risk for a family.

CFAP221 p.Lys74fs

c.222del · VCV4871845

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00735%, eas)

Conditions

Young syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 24
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 6.3	GERP 1.8, phastCons 1
Overall
CADD	24.1	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 0.00735% East Asian · 3/40,834 alleles

Filtering AF 0.00195% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000196% 3/1,534,008 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: CFAP221
Protein: p.Lys74fs
Coding: c.222del
MANE Select: NM_001271049
Type: Deletion
Location: chr2:119549163 (GRCh38)
Gene constraint: LOEUF 1.102 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.53

Full CFAP221 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Young syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Young syndrome (Orphanet):

Inheritance: Unknown
Onset: Adult

Similar variants

CFAP221 p.Leu768fs Pathogenic/Likely pathogenic same condition
CFAP221 p.Lys489fs Pathogenic same condition
CFAP221 p.Arg131Ter Pathogenic ★ same condition
CFAP221 p.Asn548fs Conflicting classifications of pathogenicity ★ same condition
CFAP221 c.2318+1G>A Pathogenic/Likely pathogenic same condition
CFAP221 p.Arg36fs Pathogenic ★ 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/cfap221-p-lys74fs (accessed [today's date]).

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