Is CCDC40 p.Arg321Gln (c.962G>A) pathogenic?

CCDC40 p.Arg321Gln (c.962G>A) is classified Uncertain significance in CCDC40 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-17). AlphaMissense: likely benign (0.068); Ultra-rare (popmax 0.0165%, mid); Associated with primary ciliary dyskinesia 15.

What condition is associated with CCDC40 p.Arg321Gln (c.962G>A)?

CCDC40 p.Arg321Gln (c.962G>A) is associated with primary ciliary dyskinesia 15, primary ciliary dyskinesia (ClinVar).

How common is CCDC40 p.Arg321Gln (c.962G>A) in the general population?

CCDC40 p.Arg321Gln (c.962G>A) 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 CCDC40 p.Arg321Gln (c.962G>A)?

AlphaMissense predicts likely benign (score 0.068) — an in-silico prediction, not a clinical call.

CCDC40 p.Arg321Gln

c.962G>A · rs114740534 · VCV1487085

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.068 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

primary ciliary dyskinesia 15

Computational evidence

Protein change
AlphaMissense	0.068	likely benign
REVEL	0.017	moderately benign-leaning
SaProt	LLR -5.68	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 -1.5	GERP -3.3
Regional constraint	o/e 0.97	unconstrained · MANE · 63 kb · p 0.29 · regional, not allelic
Overall
CADD	8.354	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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 · 1/6,062 alleles

Filtering AF 0.00207% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00183%

Overall 0.00279% 45/1,613,990 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
East Asian	0.00669%	14,956
Remaining individualsnot grpmax-eligible	0.0048%	20,836
European (non-Finnish)	0.00288%	34,706
African / African-American	0.00267%	37,510
South Asian	0.0022%	45,536

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.Arg321Gln
Coding: c.962G>A
MANE Select: NM_017950
dbSNP: rs114740534
Type: single nucleotide variant
Location: chr17:80050086 (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 15 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: primary ciliary dyskinesia

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.Arg321Ter Pathogenic ★★ same residue
CCDC40 c.1159+1G>A Likely pathogenic ★★ same condition
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-arg321gln (accessed [today's date]).

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