Is TBCD p.Arg765Trp (c.2293C>T) pathogenic?

TBCD p.Arg765Trp (c.2293C>T) is classified Uncertain significance in TBCD (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-06-25). AlphaMissense: likely benign (0.0961); Ultra-rare (popmax 0.0166%, mid); Associated with early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome.

How common is TBCD p.Arg765Trp (c.2293C>T) in the general population?

TBCD p.Arg765Trp (c.2293C>T) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

What do computational predictors say about TBCD p.Arg765Trp (c.2293C>T)?

AlphaMissense predicts likely benign (score 0.0961) — an in-silico prediction, not a clinical call.

TBCD p.Arg765Trp

Q: What condition is associated with TBCD p.Arg765Trp (c.2293C>T)?

TBCD p.Arg765Trp (c.2293C>T) is associated with early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome (ClinVar).

c.2293C>T · rs547091970 · VCV1691218

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0961 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.0961	likely benign
REVEL	0.23	benign-leaning
SaProt	LLR -11.56	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP 0.058, phastCons 0.2
Regional constraint	o/e 0.90	unconstrained · MANE · 190 kb · p 9.5e-05 · regional, not allelic
Overall
CADD	23.8	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 0.0166% Middle Eastern · 1/6,038 alleles

Filtering AF 0.00474% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00319%

Overall 0.0047% 74/1,573,072 alleles · ultra-rare exomes 67/1,420,888 · genomes 7/152,184 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.219%	456
Middle Easterngrpmax	0.0166%	6,038
Admixed American	0.011%	9,092
East Asian	0.00934%	10,710
South Asian	0.00701%	14,262
Remaining individualsnot grpmax-eligible	0.00657%	15,232
European (non-Finnish)	0.00414%	24,127
African / African-American	0.00405%	24,686

Amish 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: TBCD
Protein: p.Arg765Trp
Coding: c.2293C>T
MANE Select: NM_005993
dbSNP: rs547091970
Type: single nucleotide variant
Location: chr17:82924971 (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.Arg765Gln Likely benign ★ 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-arg765trp (accessed [today's date]).

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