Is CCDC78 p.Arg223= (c.669T>C) pathogenic?

CCDC78 p.Arg223= (c.669T>C) is classified Likely benign in CCDC78 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-09-27). Very rare (popmax 8.48e-05%, nfe); Associated with congenital myopathy with internal nuclei and atypical cores.

What condition is associated with CCDC78 p.Arg223= (c.669T>C)?

CCDC78 p.Arg223= (c.669T>C) is associated with congenital myopathy with internal nuclei and atypical cores (ClinVar).

How common is CCDC78 p.Arg223= (c.669T>C) in the general population?

CCDC78 p.Arg223= (c.669T>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

CCDC78 p.Arg223=

Q: How is Congenital myopathy with internal nuclei and atypical cores inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.669T>C · rs766296563 · VCV2193033

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

congenital myopathy with internal nuclei and atypical cores

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.028	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.62	GERP -4.6, phastCons 0.093
Overall
CADD	3.969	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,796 alleles

Overall 0.0036% 58/1,612,016 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0879%	1,138
Remaining individualsnot grpmax-eligible	0.0032%	31,204
European (non-Finnish)grpmax	8.48e-05%	1,179,796

Finnish 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: CCDC78
Protein: p.Arg223=
Coding: c.669T>C
MANE Select: NM_001378030
dbSNP: rs766296563
Type: single nucleotide variant
Location: chr16:724777 (GRCh38)
Gene constraint: LOEUF 1.615 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.65

Full CCDC78 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

congenital myopathy with internal nuclei and atypical cores — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Congenital myopathy with internal nuclei and atypical cores (Orphanet):

Inheritance: Autosomal dominant
Onset: Neonatal

Similar variants

CCDC78 p.Arg223Cys Uncertain significance ★ ⚠ same residue
CCDC78 p.Arg223Leu Uncertain significance ★ ⚠ same residue
CCDC78 p.Arg223His Likely benign ★ ⚠ same residue
CCDC78 c.1053+1G>A Uncertain significance ★★ same condition
CCDC78 c.268-3C>T Uncertain significance ★★ same condition
CCDC78 c.61-1G>A Uncertain significance ★★ same condition
CCDC78 c.61-6C>A Uncertain significance ★★ same condition
CCDC78 c.953+1G>A Uncertain significance ★★ 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/ccdc78-p-arg223 (accessed [today's date]).

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