Is CCDC78 p.Leu208Pro (c.623T>C) pathogenic?

CCDC78 p.Leu208Pro (c.623T>C) is classified Uncertain significance in CCDC78 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-21). AlphaMissense: likely pathogenic (0.5891); Absent from gnomAD v4.1; Associated with congenital myopathy with internal nuclei and atypical cores.

What condition is associated with CCDC78 p.Leu208Pro (c.623T>C)?

CCDC78 p.Leu208Pro (c.623T>C) is associated with congenital myopathy with internal nuclei and atypical cores (ClinVar).

How common is CCDC78 p.Leu208Pro (c.623T>C) in the general population?

CCDC78 p.Leu208Pro (c.623T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CCDC78 p.Leu208Pro (c.623T>C)?

AlphaMissense predicts likely pathogenic (score 0.5891) — an in-silico prediction, not a clinical call.

CCDC78 p.Leu208Pro

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.623T>C · VCV4769093

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5891 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital myopathy with internal nuclei and atypical cores

Computational evidence

Protein change
AlphaMissense	0.5891	likely pathogenic · top 6% in CCDC78
REVEL	0.265	benign-leaning
SaProt	LLR -12.67	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2.3, phastCons 1
Regional constraint	o/e 1.20	unconstrained · MANE · 3,686 bp · p 9.6e-07 · regional, not allelic
Overall
CADD	23.4	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

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.Leu208Pro
Coding: c.623T>C
MANE Select: NM_001378030
Type: single nucleotide variant
Location: chr16:724927 (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.Leu208Met Uncertain significance ★ ⚠ same residue
CCDC78 p.Leu208= 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-leu208pro (accessed [today's date]).

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