Is CCNO p.Leu221= (c.663G>A) pathogenic?

CCNO p.Leu221= (c.663G>A) is classified Likely benign in CCNO (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-12). Very rare (popmax 0.00378%, amr); Associated with primary ciliary dyskinesia.

What condition is associated with CCNO p.Leu221= (c.663G>A)?

CCNO p.Leu221= (c.663G>A) is associated with primary ciliary dyskinesia (ClinVar).

How common is CCNO p.Leu221= (c.663G>A) in the general population?

CCNO p.Leu221= (c.663G>A) is very rare (popmax 0.00378%, amr) (gnomAD).

How is Primary ciliary dyskinesia inherited?

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

CCNO p.Leu221=

c.663G>A · VCV3607009

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00378%, amr)

Conditions

primary ciliary dyskinesia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.7	GERP 1.9, phastCons 0.008
Overall
CADD	10.32	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00378% Admixed American · 2/52,892 alleles

Filtering AF 0.000627% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000235%

Overall 0.000212% 3/1,415,444 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00378%	26,446
South Asian	0.00117%	85,508

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: CCNO
Protein: p.Leu221=
Coding: c.663G>A
MANE Select: NM_021147
Type: single nucleotide variant
Location: chr5:55231765 (GRCh38)
Gene constraint: LOEUF 1.698 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.06

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

Disease context

primary ciliary dyskinesia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Primary ciliary dyskinesia (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Neonatal
Prevalence: 1-5 / 10 000 (Pakistan)

Similar variants

CCNO p.Gln103Ter Pathogenic ★★ same condition
CCNO p.Ala14Ser Uncertain significance ★★ ⚠ same condition
CCNO p.Ala202Val Uncertain significance ★★ ⚠ same condition
CCNO p.Ala230Thr Uncertain significance ★★ ⚠ same condition
CCNO p.Ala258Gly Uncertain significance ★★ ⚠ same condition
CCNO p.Arg124Leu Uncertain significance ★★ ⚠ same condition
CCNO p.Arg124Trp Uncertain significance ★★ ⚠ same condition
CCNO p.Arg133Leu Uncertain significance ★★ ⚠ 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/ccno-p-leu221 (accessed [today's date]).

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