Is CCDC65 p.Phe457fs (c.1370_1371del) pathogenic?

CCDC65 p.Phe457fs (c.13701371del) is classified Uncertain significance in CCDC65 (ClinVar, Single submitter, 1 submitter; last evaluated 2016-07-13). Rare (popmax 0.143%, eas); Associated with primary ciliary dyskinesia 27.

What condition is associated with CCDC65 p.Phe457fs (c.1370_1371del)?

CCDC65 p.Phe457fs (c.1370_1371del) is associated with primary ciliary dyskinesia 27 (ClinVar).

How common is CCDC65 p.Phe457fs (c.1370_1371del) in the general population?

CCDC65 p.Phe457fs (c.1370_1371del) is rare (popmax 0.143%, eas) (gnomAD).

How is Primary ciliary dyskinesia inherited?

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

CCDC65 p.Phe457fs

c.1370_1371del · rs1060503167 · VCV411133

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

rare (popmax 0.143%, eas)

Conditions

primary ciliary dyskinesia 27

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 (8 of 8) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.3	GERP -1.1, phastCons 1
Overall
CADD	34.0	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 0.143% East Asian · 64/44,892 alleles

Filtering AF 0.115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.104%

Overall 0.00396% 64/1,614,178 alleles · 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: CCDC65
Protein: p.Phe457fs
Coding: c.1370_1371del
MANE Select: NM_033124
dbSNP: rs1060503167
Type: Deletion
Location: chr12:48921357 (GRCh38)
Gene constraint: LOEUF 1.004 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.21 · 1 PDB

Full CCDC65 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

primary ciliary dyskinesia 27 — 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

DRC2 p.Glu165fs Pathogenic ★★ same condition
DRC2 c.1026+8_1026+9del Benign/Likely benign ★★ same condition
DRC2 p.Asn232_Tyr233insTer Pathogenic ★ same condition
DRC2 p.Leu247fs Pathogenic ★ same condition
DRC2 p.Val302fs Pathogenic ★ same condition
DRC2 p.Val323fs Pathogenic ★ same condition
DRC2 p.Lys49_Ala55del Uncertain significance ★ same condition
DRC2 c.1179+14del Benign ★ 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/ccdc65-p-phe457fs (accessed [today's date]).

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