Is CCDC8 p.Arg519fs (c.1555del) pathogenic?

CCDC8 p.Arg519fs (c.1555del) is classified Uncertain significance in CCDC8 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-09-29). Ultra-rare (popmax 0.0336%, nfe).

How common is CCDC8 p.Arg519fs (c.1555del) in the general population?

CCDC8 p.Arg519fs (c.1555del) is ultra-rare (popmax 0.0336%, nfe) (gnomAD).

CCDC8 p.Arg519fs

c.1555del · rs745914961 · VCV452737

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0336%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (1 of 1) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.7	GERP 0.65, phastCons 0.02
Overall
CADD	22.6	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0336% European (non-Finnish) · 397/1,180,026 alleles

Filtering AF 0.0309% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0298%

Overall 0.027% 435/1,614,078 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0642%	1,558
European (non-Finnish)grpmax	0.0336%	2,972
Remaining individualsnot grpmax-eligible	0.0256%	3,905
African / African-American	0.00267%	37,470
Finnishnot grpmax-eligible	0.00156%	64,046

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CCDC8
Protein: p.Arg519fs
Coding: c.1555del
MANE Select: NM_032040
dbSNP: rs745914961
Type: Deletion
Location: chr19:46411256 (GRCh38)
Gene constraint: LOEUF 1.796 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 46.83 · 1 PDB

Full CCDC8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCDC8 p.Gln327fs Pathogenic/Likely pathogenic ★★ same type
CCDC8 p.Glu337_Arg344del Uncertain significance ★★ same type
CCDC8 p.Glu350_Ala373del Uncertain significance ★★ same type
CCDC8 p.Ala323fs Likely pathogenic ★ same type
CCDC8 p.Ala353fs Likely pathogenic ★ same type
CCDC8 p.Asp247fs Likely pathogenic ★ same type
CCDC8 p.Gln68fs Likely pathogenic ★ same type
CCDC8 p.Gly95fs Likely pathogenic ★ same type

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/ccdc8-p-arg519fs (accessed [today's date]).

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