Is TBCD p.Ala554Val (c.1661C>T) pathogenic?

TBCD p.Ala554Val (c.1661C>T) is classified Pathogenic/Likely pathogenic in TBCD (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-09-10). AlphaMissense: ambiguous (0.5129); Absent from gnomAD v4.1; Associated with early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome.

How common is TBCD p.Ala554Val (c.1661C>T) in the general population?

TBCD p.Ala554Val (c.1661C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TBCD p.Ala554Val (c.1661C>T)?

AlphaMissense predicts ambiguous (score 0.5129) — an in-silico prediction, not a clinical call.

TBCD p.Ala554Val

Q: What condition is associated with TBCD p.Ala554Val (c.1661C>T)?

TBCD p.Ala554Val (c.1661C>T) is associated with early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome (ClinVar).

c.1661C>T · rs1555641324 · VCV452575

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.5129 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.5129	ambiguous
REVEL	0.424	indeterminate
SaProt	LLR -11.96	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2.4, phastCons 1
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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TBCD
Protein: p.Ala554Val
Coding: c.1661C>T
MANE Select: NM_005993
dbSNP: rs1555641324
Type: single nucleotide variant
Location: chr17:82900662 (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.Ala554= 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.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-ala554val (accessed [today's date]).

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