Is CCDC78 p.Arg397Cys (c.1189C>T) pathogenic?

CCDC78 p.Arg397Cys (c.1189C>T) is classified Benign/Likely benign in CCDC78 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-09). AlphaMissense: likely benign (0.1022); Rare (popmax 0.28%, sas); Associated with congenital myopathy with internal nuclei and atypical cores.

What condition is associated with CCDC78 p.Arg397Cys (c.1189C>T)?

CCDC78 p.Arg397Cys (c.1189C>T) is associated with congenital myopathy with internal nuclei and atypical cores (ClinVar).

How common is CCDC78 p.Arg397Cys (c.1189C>T) in the general population?

CCDC78 p.Arg397Cys (c.1189C>T) is rare (popmax 0.28%, sas) (gnomAD).

What do computational predictors say about CCDC78 p.Arg397Cys (c.1189C>T)?

AlphaMissense predicts likely benign (score 0.1022) — an in-silico prediction, not a clinical call.

CCDC78 p.Arg397Cys

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.1189C>T · rs559942514 · VCV703035

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1022 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.28%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital myopathy with internal nuclei and atypical cores

Computational evidence

Protein change
AlphaMissense	0.1022	likely benign
REVEL	0.182	moderately benign-leaning
SaProt	LLR -8.93	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 2.4	GERP -2.1, phastCons 0.98
Regional constraint	o/e 1.20	unconstrained · MANE · 3,686 bp · p 9.6e-07 · regional, not allelic
Overall
CADD	22.3	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 0.28% South Asian · 255/91,090 alleles

Filtering AF 0.252% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.241%

Overall 0.0244% 394/1,612,734 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.28%	357
Admixed American	0.0466%	2,144
Remaining individualsnot grpmax-eligible	0.0176%	5,681
European (non-Finnish)	0.00788%	12,688
African / African-American	0.00666%	15,015
East Asian	0.00446%	22,446

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.Arg397Cys
Coding: c.1189C>T
MANE Select: NM_001378030
dbSNP: rs559942514
Type: single nucleotide variant
Location: chr16:723106 (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.Arg397His Benign/Likely benign ★★ ⚠ same residue
CCDC78 p.Arg397Pro 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
CCDC78 p.Ala126Val 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-arg397cys (accessed [today's date]).

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