Is CCDC40 p.Arg1088Ser (c.3262C>A) pathogenic?

CCDC40 p.Arg1088Ser (c.3262C>A) is classified Uncertain significance in CCDC40 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-19). AlphaMissense: ambiguous (0.5192); Very rare (popmax 0.00133%, afr); Associated with primary ciliary dyskinesia.

What condition is associated with CCDC40 p.Arg1088Ser (c.3262C>A)?

CCDC40 p.Arg1088Ser (c.3262C>A) is associated with primary ciliary dyskinesia (ClinVar).

How common is CCDC40 p.Arg1088Ser (c.3262C>A) in the general population?

CCDC40 p.Arg1088Ser (c.3262C>A) is very rare (popmax 0.00133%, afr) (gnomAD).

How is Primary ciliary dyskinesia inherited?

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

What do computational predictors say about CCDC40 p.Arg1088Ser (c.3262C>A)?

AlphaMissense predicts ambiguous (score 0.5192) — an in-silico prediction, not a clinical call.

CCDC40 p.Arg1088Ser

c.3262C>A · VCV4221236

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5192 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

primary ciliary dyskinesia

Computational evidence

Protein change
AlphaMissense	0.5192	ambiguous
REVEL	0.165	moderately benign-leaning
SaProt	LLR -5.54	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 63 kb · p 0.29 · regional, not allelic
Overall
CADD	20.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,050 alleles

Overall 6.84e-05% 1/1,461,448 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.Arg1088Ser
Coding: c.3262C>A
MANE Select: NM_017950
Type: single nucleotide variant
Location: chr17:80099608 (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

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

CCDC40 p.Arg1088Cys Uncertain significance ★★ ⚠ same residue
CCDC40 p.Arg1088His Uncertain significance ★★ ⚠ same residue
CCDC40 c.1989+1G>A Pathogenic/Likely pathogenic ★★ same condition
CCDC40 c.2712-1G>T Pathogenic/Likely pathogenic ★★ same condition
CCDC40 c.855+1G>A Pathogenic/Likely pathogenic ★★ same condition
CCDC40 c.940-1G>C Pathogenic/Likely pathogenic ★★ same condition
CCDC40 c.940-2A>G Pathogenic ★★ same condition
CCDC40 p.Arg1059Ter 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-arg1088ser (accessed [today's date]).

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