Is CCDC78 p.Asp333Glu (c.999C>G) pathogenic?

CCDC78 p.Asp333Glu (c.999C>G) is classified Uncertain significance in CCDC78 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-16). AlphaMissense: likely benign (0.2133); Absent from gnomAD v4.1; Associated with congenital myopathy with internal nuclei and atypical cores.

What condition is associated with CCDC78 p.Asp333Glu (c.999C>G)?

CCDC78 p.Asp333Glu (c.999C>G) is associated with congenital myopathy with internal nuclei and atypical cores (ClinVar).

How common is CCDC78 p.Asp333Glu (c.999C>G) in the general population?

CCDC78 p.Asp333Glu (c.999C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CCDC78 p.Asp333Glu (c.999C>G)?

AlphaMissense predicts likely benign (score 0.2133) — an in-silico prediction, not a clinical call.

CCDC78 p.Asp333Glu

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.999C>G · rs1450643801 · VCV953553

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2133 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital myopathy with internal nuclei and atypical cores

Computational evidence

Protein change
AlphaMissense	0.2133	likely benign
REVEL	0.043	moderately benign-leaning
SaProt	LLR -6.39	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.45	GERP -0.79, phastCons 0.002
Regional constraint	o/e 1.20	unconstrained · MANE · 3,686 bp · p 9.6e-07 · regional, not allelic
Overall
CADD	1.043	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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: CCDC78
Protein: p.Asp333Glu
Coding: c.999C>G
MANE Select: NM_001378030
dbSNP: rs1450643801
Type: single nucleotide variant
Location: chr16:724160 (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

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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-asp333glu (accessed [today's date]).

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