Is TBCD p.Arg436Ter (c.1306C>T) pathogenic?

TBCD p.Arg436Ter (c.1306C>T) is classified Pathogenic in TBCD (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-29). Very rare (popmax 0.000848%, nfe); Associated with early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome.

How common is TBCD p.Arg436Ter (c.1306C>T) in the general population?

TBCD p.Arg436Ter (c.1306C>T) is very rare (popmax 0.000848%, nfe) (gnomAD).

TBCD p.Arg436Ter

Q: What condition is associated with TBCD p.Arg436Ter (c.1306C>T)?

TBCD p.Arg436Ter (c.1306C>T) is associated with early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome (ClinVar).

c.1306C>T · rs1428485417 · VCV1700434

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000848%, 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/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 13 of 39
Splicing
SpliceAI	Δ0.20	donor loss · deltas
Pangolin	Δ0.35	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 3.6	GERP 0.55, phastCons 1
Overall
CADD	37.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000848% European (non-Finnish) · 10/1,179,076 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000313%

Overall 0.000745% 12/1,611,014 alleles · very rare exomes 10/1,459,394 · genomes 2/151,620 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,784
European (non-Finnish)grpmax	0.000848%	117,908

Ashkenazi Jewish 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.Arg436Ter
Coding: c.1306C>T
MANE Select: NM_005993
dbSNP: rs1428485417
Type: single nucleotide variant
Location: chr17:82814922 (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.Arg436Gln Uncertain significance ★ ⚠ same residue
TBCD p.Arg436= 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

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-arg436ter (accessed [today's date]).

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