Is CCDC78 p.Glu289Val (c.866A>T) pathogenic?

CCDC78 p.Glu289Val (c.866A>T) is classified Conflicting classifications of pathogenicity in CCDC78 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-15). AlphaMissense: likely pathogenic (0.8256); Ultra-rare (popmax 0.0694%, afr); Associated with congenital myopathy with internal nuclei and atypical cores.

What condition is associated with CCDC78 p.Glu289Val (c.866A>T)?

CCDC78 p.Glu289Val (c.866A>T) is associated with congenital myopathy with internal nuclei and atypical cores (ClinVar).

How common is CCDC78 p.Glu289Val (c.866A>T) in the general population?

CCDC78 p.Glu289Val (c.866A>T) is ultra-rare (popmax 0.0694%, afr) (gnomAD).

What do computational predictors say about CCDC78 p.Glu289Val (c.866A>T)?

AlphaMissense predicts likely pathogenic (score 0.8256) — an in-silico prediction, not a clinical call.

CCDC78 p.Glu289Val

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.866A>T · rs371760552 · VCV651051

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8256 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0694%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital myopathy with internal nuclei and atypical cores

Computational evidence

Protein change
AlphaMissense	0.8256	likely pathogenic · top 2% in CCDC78
REVEL	0.286	benign-leaning
SaProt	LLR -7.18	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 2, phastCons 1
Regional constraint	o/e 1.20	unconstrained · MANE · 3,686 bp · p 9.6e-07 · regional, not allelic
Overall
CADD	26.6	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

Grpmax group 0.0694% African / African-American · 52/74,930 alleles

Filtering AF 0.0543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.049%

Overall 0.00472% 76/1,610,428 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0694%	1,441
Admixed American	0.0217%	4,615
Remaining individualsnot grpmax-eligible	0.0128%	7,806
European (non-Finnish)	0.000254%	393,318

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.Glu289Val
Coding: c.866A>T
MANE Select: NM_001378030
dbSNP: rs371760552
Type: single nucleotide variant
Location: chr16:724409 (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

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CCDC78 c.61-6C>A Uncertain significance ★★ same condition
CCDC78 c.953+1G>A Uncertain significance ★★ same condition
CCDC78 p.Ala126Val Uncertain significance ★★ ⚠ same condition
CCDC78 p.Ala188Ser Uncertain significance ★★ ⚠ same condition
CCDC78 p.Ala227Val 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-glu289val (accessed [today's date]).

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