Is CCDC78 p.Trp252Arg (c.754T>C) pathogenic?

CCDC78 p.Trp252Arg (c.754T>C) is classified Benign in CCDC78 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0414); Common (popmax 82.3%, eas) — too common for a highly-penetrant pathogenic allele; Associated with congenital myopathy with internal nuclei and atypical cores.

What condition is associated with CCDC78 p.Trp252Arg (c.754T>C)?

CCDC78 p.Trp252Arg (c.754T>C) is associated with congenital myopathy with internal nuclei and atypical cores (ClinVar).

What do computational predictors say about CCDC78 p.Trp252Arg (c.754T>C)?

AlphaMissense predicts likely benign (score 0.0414) — an in-silico prediction, not a clinical call.

CCDC78 p.Trp252Arg

Q: How common is CCDC78 p.Trp252Arg (c.754T>C) in the general population?

CCDC78 p.Trp252Arg (c.754T>C) is common (popmax 82.3%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

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.754T>C · rs2071950 · VCV128631

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0414 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 82.3%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital myopathy with internal nuclei and atypical cores

Computational evidence

Protein change
AlphaMissense	0.0414	likely benign
REVEL	0.241	benign-leaning
SaProt	LLR -5.29	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	GERP -4.1, phastCons 0.98
Regional constraint	o/e 1.20	unconstrained · MANE · 3,686 bp · p 9.6e-07 · regional, not allelic
Overall
CADD	0.847	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 82.3% East Asian · 36,903/44,832 alleles

Filtering AF 81.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 81.3%

Overall 52.6% 847,352/1,609,756 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	82.3%	1
South Asian	79.8%	1
Admixed American	68.6%	1
African / African-American	66.6%	2
Finnishnot grpmax-eligible	60.6%	2
Remaining individualsnot grpmax-eligible	52.6%	2
European (non-Finnish)	47.7%	2
Amishnot grpmax-eligible	45.6%	2
Ashkenazi Jewishnot grpmax-eligible	40.4%	2
Middle Eastern	38.6%	3

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.Trp252Arg
Coding: c.754T>C
MANE Select: NM_001378030
dbSNP: rs2071950
Type: single nucleotide variant
Location: chr16:724692 (GRCh38)
Gene constraint: LOEUF 1.615 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.65
Residue 252: a UniProt-annotated variant site (in)

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.Trp252Ter Conflicting classifications of pathogenicity ★ same residue
CCDC78 p.Trp252Gln Benign/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
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-trp252arg (accessed [today's date]).

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