Is CCDC78 p.Arg288Ser (c.862C>A) pathogenic?

CCDC78 p.Arg288Ser (c.862C>A) is classified Uncertain significance in CCDC78 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-16). AlphaMissense: likely pathogenic (0.8818); Very rare (popmax 8.47e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CCDC78 p.Arg288Ser (c.862C>A)?

CCDC78 p.Arg288Ser (c.862C>A) is associated with Inborn genetic diseases, congenital myopathy with internal nuclei and atypical cores (ClinVar).

How common is CCDC78 p.Arg288Ser (c.862C>A) in the general population?

CCDC78 p.Arg288Ser (c.862C>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CCDC78 p.Arg288Ser (c.862C>A)?

AlphaMissense predicts likely pathogenic (score 0.8818) — an in-silico prediction, not a clinical call.

CCDC78 p.Arg288Ser

c.862C>A · rs764179609 · VCV2720308

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8818 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8818	likely pathogenic · top 1% in CCDC78
REVEL	0.352	indeterminate
SaProt	LLR -7.48	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.28 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.8	GERP -0.47, phastCons 1
Regional constraint	o/e 1.20	unconstrained · MANE · 3,686 bp · p 9.6e-07 · regional, not allelic
Overall
CADD	24.9	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 8.47e-05% European (non-Finnish) · 1/1,179,950 alleles

Overall 6.86e-05% 1/1,457,696 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.Arg288Ser
Coding: c.862C>A
MANE Select: NM_001378030
dbSNP: rs764179609
Type: single nucleotide variant
Location: chr16:724413 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: congenital myopathy with internal nuclei and atypical cores

Similar variants

CCDC78 p.Arg288Cys Uncertain significance ★★ ⚠ same residue
CCDC78 p.Arg288His 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-arg288ser (accessed [today's date]).

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