Is TBCD p.Pro1122Leu (c.3365C>T) pathogenic?

TBCD p.Pro1122Leu (c.3365C>T) is classified Conflicting classifications of pathogenicity in TBCD (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2024-04-18). AlphaMissense: likely benign (0.2455); Ultra-rare (popmax 0.0178%, eas); Associated with early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome.

How common is TBCD p.Pro1122Leu (c.3365C>T) in the general population?

TBCD p.Pro1122Leu (c.3365C>T) is ultra-rare (popmax 0.0178%, eas) (gnomAD).

What do computational predictors say about TBCD p.Pro1122Leu (c.3365C>T)?

AlphaMissense predicts likely benign (score 0.2455) — an in-silico prediction, not a clinical call.

TBCD p.Pro1122Leu

Q: What condition is associated with TBCD p.Pro1122Leu (c.3365C>T)?

TBCD p.Pro1122Leu (c.3365C>T) is associated with early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome (ClinVar).

c.3365C>T · rs755177846 · VCV268171

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2455 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0178%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.2455	likely benign
REVEL	0.364	indeterminate
SaProt	LLR -11.23	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.5, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 190 kb · p 9.5e-05 · regional, not allelic
Overall
CADD	25.6	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 0.0178% East Asian · 8/44,864 alleles

Filtering AF 0.00884% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00641%

Overall 0.00186% 30/1,611,758 alleles · ultra-rare exomes 23/1,459,524 · genomes 7/152,234 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0338%	2,958
East Asiangrpmax	0.0178%	5,608
African / African-American	0.00668%	14,977
South Asian	0.0022%	45,447
Remaining individualsnot grpmax-eligible	0.00161%	62,300
European (non-Finnish)	0.000339%	294,943

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.Pro1122Leu
Coding: c.3365C>T
MANE Select: NM_005993
dbSNP: rs755177846
Type: single nucleotide variant
Location: chr17:82938132 (GRCh38)
Gene constraint: LOEUF 0.763 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.45 · 6 PDB
Residue 1122: a UniProt-annotated variant site (in pebat; severely decreased protein abundance; does not affect localization to centrosome; decreased interaction with arl2; decreased interaction with tbce; decreased interaction with beta tubulin)

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.Pro1122= 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-pro1122leu (accessed [today's date]).

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