Is CCDC78 p.Arg231Trp (c.691C>T) pathogenic?

CCDC78 p.Arg231Trp (c.691C>T) is classified Uncertain significance in CCDC78 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-27). AlphaMissense: likely benign (0.1254); Very rare (popmax 0.0017%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CCDC78 p.Arg231Trp (c.691C>T)?

CCDC78 p.Arg231Trp (c.691C>T) is associated with Inborn genetic diseases, congenital myopathy with internal nuclei and atypical cores (ClinVar).

How common is CCDC78 p.Arg231Trp (c.691C>T) in the general population?

CCDC78 p.Arg231Trp (c.691C>T) is very rare (popmax 0.0017%, nfe) (gnomAD).

What do computational predictors say about CCDC78 p.Arg231Trp (c.691C>T)?

AlphaMissense predicts likely benign (score 0.1254) — an in-silico prediction, not a clinical call.

CCDC78 p.Arg231Trp

c.691C>T · rs527479144 · VCV2321682

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1254 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0017%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1254	likely benign
REVEL	0.102	moderately benign-leaning
SaProt	LLR -9.55	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 1.8	GERP -2.8, phastCons 0.95
Regional constraint	o/e 1.20	unconstrained · MANE · 3,686 bp · p 9.6e-07 · regional, not allelic
Overall
CADD	21.3	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 0.0017% European (non-Finnish) · 20/1,179,766 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0009%

Overall 0.00164% 24/1,459,742 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00481%	20,810
European (non-Finnish)grpmax	0.0017%	58,988
African / African-American	0.00133%	75,058

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg231Trp
Coding: c.691C>T
MANE Select: NM_001378030
dbSNP: rs527479144
Type: single nucleotide variant
Location: chr16:724755 (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.Arg231Gly Uncertain significance ★ ⚠ same residue
CCDC78 p.Arg231Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
CCDC78 p.Arg231Gln 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

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-arg231trp (accessed [today's date]).

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