Is CCDC40 p.Ser540Pro (c.1618T>C) pathogenic?

CCDC40 p.Ser540Pro (c.1618T>C) is classified Uncertain significance in CCDC40 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-11-07). AlphaMissense: likely pathogenic (0.8712); Absent from gnomAD v4.1; Associated with primary ciliary dyskinesia.

What condition is associated with CCDC40 p.Ser540Pro (c.1618T>C)?

CCDC40 p.Ser540Pro (c.1618T>C) is associated with primary ciliary dyskinesia (ClinVar).

How common is CCDC40 p.Ser540Pro (c.1618T>C) in the general population?

CCDC40 p.Ser540Pro (c.1618T>C) is absent from gnomAD v4.1 (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.Ser540Pro (c.1618T>C)?

AlphaMissense predicts likely pathogenic (score 0.8712) — an in-silico prediction, not a clinical call.

CCDC40 p.Ser540Pro

c.1618T>C · rs1598533116 · VCV655650

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8712 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

primary ciliary dyskinesia

Computational evidence

Protein change
AlphaMissense	0.8712	likely pathogenic · top 2% in CCDC40
REVEL	0.239	benign-leaning
SaProt	LLR -11.86	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 2.1, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 63 kb · p 0.29 · regional, not allelic
Overall
CADD	24.6	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CCDC40
Protein: p.Ser540Pro
Coding: c.1618T>C
MANE Select: NM_017950
dbSNP: rs1598533116
Type: single nucleotide variant
Location: chr17:80081601 (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 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
CCDC40 p.Arg321Ter 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-ser540pro (accessed [today's date]).

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