Is TBCD p.Arg294Trp (c.880C>T) pathogenic?

TBCD p.Arg294Trp (c.880C>T) is classified Conflicting classifications of pathogenicity in TBCD (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-18). AlphaMissense: ambiguous (0.44); Very rare (popmax 0.00224%, eas); Associated with early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome.

How common is TBCD p.Arg294Trp (c.880C>T) in the general population?

TBCD p.Arg294Trp (c.880C>T) is very rare (popmax 0.00224%, eas) (gnomAD).

What do computational predictors say about TBCD p.Arg294Trp (c.880C>T)?

AlphaMissense predicts ambiguous (score 0.44) — an in-silico prediction, not a clinical call.

TBCD p.Arg294Trp

Q: What condition is associated with TBCD p.Arg294Trp (c.880C>T)?

TBCD p.Arg294Trp (c.880C>T) is associated with early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome (ClinVar).

c.880C>T · rs1064796675 · VCV423874

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.44 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00224%, eas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome

Computational evidence

Protein change
AlphaMissense	0.44	ambiguous
REVEL	0.688	pathogenic-leaning
SaProt	LLR -12.97	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP 2, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 190 kb · p 9.5e-05 · regional, not allelic
Overall
CADD	29.5	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 0.00224% East Asian · 1/44,722 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000682% 11/1,611,742 alleles · very rare exomes 10/1,459,668 · genomes 1/152,074 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00224%	44,722
African / African-American	0.00134%	74,740
South Asian	0.0011%	90,954
European (non-Finnish)	0.000678%	147,407

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: TBCD
Protein: p.Arg294Trp
Coding: c.880C>T
MANE Select: NM_005993
dbSNP: rs1064796675
Type: single nucleotide variant
Location: chr17:82800926 (GRCh38)
Gene constraint: LOEUF 0.763 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.45 · 6 PDB

Full TBCD gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TBCD p.Arg294Gln Likely pathogenic ★ ⚠ same residue
TBCD c.1224-2A>G Pathogenic/Likely pathogenic ★★ same condition
TBCD c.2007-2A>G Likely pathogenic ★★ same condition
TBCD p.Ala475Thr Pathogenic/Likely pathogenic ★★ same condition
TBCD p.Ala554Val Pathogenic/Likely pathogenic ★★ same condition
TBCD p.Arg303Ter Pathogenic/Likely pathogenic ★★ same condition
TBCD p.Arg323Ter Pathogenic/Likely pathogenic ★★ same condition
TBCD p.Arg436Ter Pathogenic ★★ 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/tbcd-p-arg294trp (accessed [today's date]).

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