Is CCDC40 p.Ser581fs (c.1741_1760del) pathogenic?

CCDC40 p.Ser581fs (c.17411760del) is classified Pathogenic in CCDC40 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-18). Very rare (popmax 0.000254%, nfe); Associated with CCDC40-related disorder.

What condition is associated with CCDC40 p.Ser581fs (c.1741_1760del)?

CCDC40 p.Ser581fs (c.1741_1760del) is associated with CCDC40-related disorder, primary ciliary dyskinesia (ClinVar).

How common is CCDC40 p.Ser581fs (c.1741_1760del) in the general population?

CCDC40 p.Ser581fs (c.1741_1760del) is very rare (popmax 0.000254%, nfe) (gnomAD).

CCDC40 p.Ser581fs

c.1741_1760del · rs1487064371 · VCV2720299

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Conditions

CCDC40-related disorder

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 11 of 20
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.1	GERP 1.1, phastCons 1
Overall
CADD	33.0	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 0.000254% European (non-Finnish) · 3/1,180,018 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,614,022 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: CCDC40
Protein: p.Ser581fs
Coding: c.1741_1760del
MANE Select: NM_017950
dbSNP: rs1487064371
Type: Deletion
Location: chr17:80081721 (GRCh38)
Gene constraint: LOEUF 0.962 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 71.70 · 1 PDB

Full CCDC40 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

CCDC40-related disorder

Also linked: primary ciliary dyskinesia

Similar variants

CCDC40 p.Ala83fs Pathogenic ★★ same condition
CCDC40 p.Arg1053fs Pathogenic/Likely pathogenic ★★ same condition
CCDC40 p.Gln524fs Pathogenic ★★ same condition
CCDC40 p.Gly728fs Pathogenic/Likely pathogenic ★★ same condition
CCDC40 p.Ile473fs Pathogenic ★★ same condition
CCDC40 p.Lys803fs Pathogenic ★★ same condition
CCDC40 p.Lys918fs Pathogenic/Likely pathogenic ★★ same condition
CCDC40 p.Phe1044fs Pathogenic/Likely pathogenic ★★ 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/ccdc40-p-ser581fs (accessed [today's date]).

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