Is TBCD p.Pro1042= (c.3126G>A) pathogenic?

TBCD p.Pro1042= (c.3126G>A) is classified Conflicting classifications of pathogenicity in TBCD (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-09-22). Rare (popmax 0.44%, sas); Associated with early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome.

How common is TBCD p.Pro1042= (c.3126G>A) in the general population?

TBCD p.Pro1042= (c.3126G>A) is rare (popmax 0.44%, sas) (gnomAD).

TBCD p.Pro1042=

Q: What condition is associated with TBCD p.Pro1042= (c.3126G>A)?

TBCD p.Pro1042= (c.3126G>A) is associated with early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome, Thiel-Behnke corneal dystrophy (ClinVar).

c.3126G>A · rs369672739 · VCV587405

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.44%, sas)

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 -4.9	GERP -2.6
Overall
CADD	4.2	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.44% South Asian · 400/90,886 alleles

Filtering AF 0.405% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.391%

Overall 0.0264% 426/1,613,462 alleles · rare exomes 401/1,461,196 · genomes 25/152,266 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.44%	227
Remaining individualsnot grpmax-eligible	0.0144%	6,942
Admixed American	0.00333%	29,992
East Asian	0.00223%	44,878
European (non-Finnish)	0.00119%	84,272

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.Pro1042=
Coding: c.3126G>A
MANE Select: NM_005993
dbSNP: rs369672739
Type: single nucleotide variant
Location: chr17:82932670 (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

Also linked: Thiel-Behnke corneal dystrophy

Similar variants

TBCD p.Pro1042Leu Conflicting classifications of pathogenicity ★ ⚠ 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-pro1042 (accessed [today's date]).

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