Is CCDC40 p.Ala83fs (c.248del) pathogenic?

CCDC40 p.Ala83fs (c.248del) is classified Pathogenic in CCDC40 (ClinVar, Multiple submitters, 25 submitters; last evaluated 2026-01-20). Ultra-rare (popmax 0.0737%, nfe); Associated with CCDC40-related disorder.

What condition is associated with CCDC40 p.Ala83fs (c.248del)?

CCDC40 p.Ala83fs (c.248del) is associated with CCDC40-related disorder, primary ciliary dyskinesia 15, primary ciliary dyskinesia (ClinVar).

How common is CCDC40 p.Ala83fs (c.248del) in the general population?

CCDC40 p.Ala83fs (c.248del) is ultra-rare (popmax 0.0737%, nfe) (gnomAD).

CCDC40 p.Ala83fs

c.248del · rs397515393 · VCV31069

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 25 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0737%, 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 3 of 20
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -1.9	GERP -1.6
Overall
CADD	2.164	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 0.0737% European (non-Finnish) · 860/1,167,354 alleles

Filtering AF 0.0695% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0679%

Overall 0.0563% 901/1,600,206 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0737%	1,357
Remaining individualsnot grpmax-eligible	0.0226%	4,433
African / African-American	0.0174%	5,748
Ashkenazi Jewishnot grpmax-eligible	0.0135%	7,384
Admixed American	0.0133%	7,499
Finnishnot grpmax-eligible	0.00156%	63,980
South Asian	0.0011%	90,806

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.Ala83fs
Coding: c.248del
MANE Select: NM_017950
dbSNP: rs397515393
Type: Deletion
Location: chr17:80039966 (GRCh38)
Gene constraint: LOEUF 0.962 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 71.70 · 1 PDB
Residue 83: the 'disordered' region

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

Disease context

CCDC40-related disorder

Also linked: primary ciliary dyskinesia 15 primary ciliary dyskinesia

Similar variants

CCDC40 c.2449+2_2449+5del Pathogenic/Likely 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-ala83fs (accessed [today's date]).

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