Is CCDC78 p.Arg348Trp (c.1042C>T) pathogenic?

CCDC78 p.Arg348Trp (c.1042C>T) is classified Uncertain significance in CCDC78 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-11). AlphaMissense: likely benign (0.094); Very rare (popmax 0.00299%, nfe); Associated with congenital myopathy with internal nuclei and atypical cores.

What condition is associated with CCDC78 p.Arg348Trp (c.1042C>T)?

CCDC78 p.Arg348Trp (c.1042C>T) is associated with congenital myopathy with internal nuclei and atypical cores (ClinVar).

How common is CCDC78 p.Arg348Trp (c.1042C>T) in the general population?

CCDC78 p.Arg348Trp (c.1042C>T) is very rare (popmax 0.00299%, nfe) (gnomAD).

What do computational predictors say about CCDC78 p.Arg348Trp (c.1042C>T)?

AlphaMissense predicts likely benign (score 0.094) — an in-silico prediction, not a clinical call.

CCDC78 p.Arg348Trp

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.1042C>T · rs761094524 · VCV2715056

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.094 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00299%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital myopathy with internal nuclei and atypical cores

Computational evidence

Protein change
AlphaMissense	0.094	likely benign
REVEL	0.096	moderately benign-leaning
SaProt	LLR -7.27	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.37 · evaluated, not missing
Pangolin	Δ0.30	loss · gain 0.00 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP -1.9	GERP -0.86
Regional constraint	o/e 1.20	unconstrained · MANE · 3,686 bp · p 9.6e-07 · regional, not allelic
Overall
CADD	18.38	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

Grpmax group 0.00299% European (non-Finnish) · 35/1,170,988 alleles

Filtering AF 0.00217% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00192%

Overall 0.00219% 35/1,595,406 alleles · very rare

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.Arg348Trp
Coding: c.1042C>T
MANE Select: NM_001378030
dbSNP: rs761094524
Type: single nucleotide variant
Location: chr16:724117 (GRCh38)
Gene constraint: LOEUF 1.615 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.65
Residue 348: the 'disordered' region

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.Arg348= Likely benign ★★ same residue
CCDC78 p.Arg348Gln Likely benign ★★ same residue
CCDC78 p.Arg348Leu Uncertain significance ★ ⚠ 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-arg348trp (accessed [today's date]).

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