Is CCDC40 p.Lys375Gln (c.1123A>C) pathogenic?

CCDC40 p.Lys375Gln (c.1123A>C) is classified Benign/Likely benign in CCDC40 (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.0918); Low-frequency (popmax 3.02%, afr); Associated with primary ciliary dyskinesia.

What condition is associated with CCDC40 p.Lys375Gln (c.1123A>C)?

CCDC40 p.Lys375Gln (c.1123A>C) is associated with primary ciliary dyskinesia, primary ciliary dyskinesia 15 (ClinVar).

How common is CCDC40 p.Lys375Gln (c.1123A>C) in the general population?

CCDC40 p.Lys375Gln (c.1123A>C) is low-frequency (popmax 3.02%, 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.Lys375Gln (c.1123A>C)?

AlphaMissense predicts likely benign (score 0.0918) — an in-silico prediction, not a clinical call.

CCDC40 p.Lys375Gln

c.1123A>C · rs61734951 · VCV241230

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

AlphaMissense

likely benign

0.0918 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 3.02%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

primary ciliary dyskinesia

Computational evidence

Protein change
AlphaMissense	0.0918	likely benign
REVEL	0.019	moderately benign-leaning
SaProt	LLR -5.52	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 0.091	GERP -3.3
Regional constraint	o/e 0.97	unconstrained · MANE · 63 kb · p 0.29 · regional, not allelic
Overall
CADD	1.039	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 3.02% African / African-American · 2,244/74,352 alleles

Filtering AF 2.91% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.87%

Overall 0.171% 2,716/1,590,146 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	3.02%	33
Middle Eastern	0.269%	372
Admixed American	0.251%	399
Remaining individualsnot grpmax-eligible	0.21%	477
European (non-Finnish)	0.0158%	6,325
South Asian	0.00565%	17,695

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.Lys375Gln
Coding: c.1123A>C
MANE Select: NM_017950
dbSNP: rs61734951
Type: single nucleotide variant
Location: chr17:80050247 (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

Also linked: primary ciliary dyskinesia 15

For Primary ciliary dyskinesia (Orphanet):

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

Similar variants

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
CCDC40 p.Arg301Ter 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-lys375gln (accessed [today's date]).

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