Is CCDC39 p.Ser625Ile (c.1874G>T) pathogenic?

CCDC39 p.Ser625Ile (c.1874G>T) is classified Conflicting classifications of pathogenicity in CCDC39 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-12-14). AlphaMissense: likely benign (0.2268); Very rare (popmax 0.00658%, nfe); Associated with CCDC39-related disorder.

What condition is associated with CCDC39 p.Ser625Ile (c.1874G>T)?

CCDC39 p.Ser625Ile (c.1874G>T) is associated with CCDC39-related disorder, primary ciliary dyskinesia 14, primary ciliary dyskinesia (ClinVar).

How common is CCDC39 p.Ser625Ile (c.1874G>T) in the general population?

CCDC39 p.Ser625Ile (c.1874G>T) is very rare (popmax 0.00658%, nfe) (gnomAD).

What do computational predictors say about CCDC39 p.Ser625Ile (c.1874G>T)?

AlphaMissense predicts likely benign (score 0.2268) — an in-silico prediction, not a clinical call.

CCDC39 p.Ser625Ile

c.1874G>T · rs769223754 · VCV228475

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2268 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00658%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CCDC39-related disorder

Computational evidence

Protein change
AlphaMissense	0.2268	likely benign
REVEL	0.244	benign-leaning
SaProt	LLR -6.67	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.93	donor loss at this position · masked 0 · deltas
Pangolin	Δ0.78	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 5.8	GERP 2.4, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 64 kb · p 0.72 · regional, not allelic
Overall
CADD	32.0	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 0.00658% European (non-Finnish) · 76/1,155,770 alleles

Filtering AF 0.00539% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00492%

Overall 0.00503% 79/1,569,294 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00658%	15,208
Finnishnot grpmax-eligible	0.00318%	31,414
Remaining individualsnot grpmax-eligible	0.00166%	60,366

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.Ser625Ile
Coding: c.1874G>T
MANE Select: NM_181426
dbSNP: rs769223754
Type: single nucleotide variant
Location: chr3:180641993 (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

CCDC39-related disorder

Also linked: primary ciliary dyskinesia 14 primary ciliary dyskinesia

Similar variants

CCDC39 p.Ser625Asn Uncertain significance ★ ⚠ 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-ser625ile (accessed [today's date]).

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