Is CCDC39 p.Arg463Trp (c.1387C>T) pathogenic?

CCDC39 p.Arg463Trp (c.1387C>T) is classified Uncertain significance in CCDC39 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-04-14). AlphaMissense: likely benign (0.2167); Ultra-rare (popmax 0.0165%, mid); Associated with primary ciliary dyskinesia.

What condition is associated with CCDC39 p.Arg463Trp (c.1387C>T)?

CCDC39 p.Arg463Trp (c.1387C>T) is associated with primary ciliary dyskinesia, primary ciliary dyskinesia 14 (ClinVar).

How common is CCDC39 p.Arg463Trp (c.1387C>T) in the general population?

CCDC39 p.Arg463Trp (c.1387C>T) is ultra-rare (popmax 0.0165%, mid) (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.Arg463Trp (c.1387C>T)?

AlphaMissense predicts likely benign (score 0.2167) — an in-silico prediction, not a clinical call.

CCDC39 p.Arg463Trp

c.1387C>T · rs368870111 · VCV452875

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2167 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

primary ciliary dyskinesia

Computational evidence

Protein change
AlphaMissense	0.2167	likely benign
REVEL	0.307	indeterminate
SaProt	LLR -11.40	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 0.27, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 64 kb · p 0.72 · regional, not allelic
Overall
CADD	25.6	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 0.0165% Middle Eastern · 1/6,050 alleles

Filtering AF 0.0114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0108%

Overall 0.0102% 164/1,600,436 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,050
European (non-Finnish)	0.0132%	7,579
African / African-American	0.00543%	18,403
Admixed American	0.00516%	19,394
Remaining individualsnot grpmax-eligible	0.00161%	62,056

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.Arg463Trp
Coding: c.1387C>T
MANE Select: NM_181426
dbSNP: rs368870111
Type: single nucleotide variant
Location: chr3:180647219 (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.Arg463Gln Uncertain significance ★★ ⚠ same residue
CCDC39 p.Arg463= Likely benign ★ 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

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-arg463trp (accessed [today's date]).

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