Is CCDC39 p.Ile224Val (c.670A>G) pathogenic?

CCDC39 p.Ile224Val (c.670A>G) is classified Conflicting classifications of pathogenicity in CCDC39 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-05-08). AlphaMissense: likely benign (0.2375); Ultra-rare (popmax 0.0637%, sas); Associated with primary ciliary dyskinesia.

What condition is associated with CCDC39 p.Ile224Val (c.670A>G)?

CCDC39 p.Ile224Val (c.670A>G) is associated with primary ciliary dyskinesia, primary ciliary dyskinesia 14 (ClinVar).

How common is CCDC39 p.Ile224Val (c.670A>G) in the general population?

CCDC39 p.Ile224Val (c.670A>G) is ultra-rare (popmax 0.0637%, sas) (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 CCDC39 p.Ile224Val (c.670A>G)?

AlphaMissense predicts likely benign (score 0.2375) — an in-silico prediction, not a clinical call.

CCDC39 p.Ile224Val

c.670A>G · rs544311014 · VCV1405756

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2375 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0637%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

primary ciliary dyskinesia

Computational evidence

Protein change
AlphaMissense	0.2375	likely benign
REVEL	0.087	moderately benign-leaning
SaProt	LLR -5.43	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 64 kb · p 0.72 · regional, not allelic
Overall
CADD	23.0	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 0.0637% South Asian · 58/91,060 alleles

Filtering AF 0.0505% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0458%

Overall 0.00415% 67/1,613,448 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0637%	1,570
Remaining individualsnot grpmax-eligible	0.0112%	8,923
East Asian	0.00223%	44,784
European (non-Finnish)	8.48e-05%	1,179,567

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: CCDC39
Protein: p.Ile224Val
Coding: c.670A>G
MANE Select: NM_181426
dbSNP: rs544311014
Type: single nucleotide variant
Location: chr3:180659520 (GRCh38)
Gene constraint: LOEUF 1.226 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 79.23 · 1 PDB

Full CCDC39 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

Also linked: primary ciliary dyskinesia 14

For Primary ciliary dyskinesia (Orphanet):

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

Similar variants

CCDC39 p.Ile224Ter Pathogenic ★ same residue
CCDC39 c.1034+2T>A Pathogenic/Likely pathogenic ★★ same condition
CCDC39 c.1167+1261A>G Pathogenic/Likely pathogenic ★★ same condition
CCDC39 c.1362+1G>A Likely pathogenic ★★ same condition
CCDC39 c.1999-2A>T Pathogenic/Likely pathogenic ★★ same condition
CCDC39 c.210+2T>C Pathogenic ★★ same condition
CCDC39 c.357+1G>C Pathogenic ★★ same condition
CCDC39 c.516+1G>A 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/ccdc39-p-ile224val (accessed [today's date]).

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