Is TBCD p.Pro935Arg (c.2804C>G) pathogenic?

TBCD p.Pro935Arg (c.2804C>G) is classified Uncertain significance in TBCD (ClinVar, Single submitter, 1 submitter; last evaluated 2020-06-19). AlphaMissense: likely benign (0.0878); Very rare (popmax 0.00439%, sas); Associated with early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome.

How common is TBCD p.Pro935Arg (c.2804C>G) in the general population?

TBCD p.Pro935Arg (c.2804C>G) is very rare (popmax 0.00439%, sas) (gnomAD).

What do computational predictors say about TBCD p.Pro935Arg (c.2804C>G)?

AlphaMissense predicts likely benign (score 0.0878) — an in-silico prediction, not a clinical call.

TBCD p.Pro935Arg

Q: What condition is associated with TBCD p.Pro935Arg (c.2804C>G)?

TBCD p.Pro935Arg (c.2804C>G) is associated with early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome (ClinVar).

c.2804C>G · rs771721082 · VCV2436967

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0878 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.0878	likely benign
REVEL	0.054	moderately benign-leaning
SaProt	LLR -8.23	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP 1.3, phastCons 0.19
Regional constraint	o/e 0.90	unconstrained · MANE · 190 kb · p 9.5e-05 · regional, not allelic
Overall
CADD	18.32	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00439% South Asian · 4/91,068 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000248% 4/1,613,922 alleles · very rare exomes 4/1,461,668 · genomes 0/152,254 · joint denominator

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.Pro935Arg
Coding: c.2804C>G
MANE Select: NM_005993
dbSNP: rs771721082
Type: single nucleotide variant
Location: chr17:82929223 (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-pro935arg (accessed [today's date]).

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