Is TBCD p.Asp1149= (c.3447C>T) pathogenic?

TBCD p.Asp1149= (c.3447C>T) is classified Conflicting classifications of pathogenicity in TBCD (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-19). Ultra-rare (popmax 0.0875%, nfe); Associated with early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome.

How common is TBCD p.Asp1149= (c.3447C>T) in the general population?

TBCD p.Asp1149= (c.3447C>T) is ultra-rare (popmax 0.0875%, nfe) (gnomAD).

TBCD p.Asp1149=

Q: What condition is associated with TBCD p.Asp1149= (c.3447C>T)?

TBCD p.Asp1149= (c.3447C>T) is associated with early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome (ClinVar).

c.3447C>T · rs183455339 · VCV1632424

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0875%, nfe)

Conditions

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

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -15	GERP -3.6
Overall
CADD	0.084	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0875% European (non-Finnish) · 1,032/1,179,832 alleles

Filtering AF 0.083% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0812%

Overall 0.069% 1,113/1,613,612 alleles · ultra-rare exomes 1,050/1,461,274 · genomes 63/152,338 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0875%	1,143
Remaining individualsnot grpmax-eligible	0.0656%	1,524
Admixed American	0.0433%	2,307
African / African-American	0.016%	6,254
East Asian	0.00223%	44,888
South Asian	0.0011%	90,964

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.Asp1149=
Coding: c.3447C>T
MANE Select: NM_005993
dbSNP: rs183455339
Type: single nucleotide variant
Location: chr17:82939444 (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 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
TBCD p.Arg772Cys Pathogenic/Likely 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-asp1149 (accessed [today's date]).

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