Is TBCD p.His77Arg (c.230A>G) pathogenic?

TBCD p.His77Arg (c.230A>G) is classified Pathogenic/Likely pathogenic in TBCD (ClinVar, Multiple submitters, 6 submitters; last evaluated 2024-11-11). AlphaMissense: likely benign (0.3093); Very rare (popmax 0.00447%, eas); Associated with TBCD-related disorder.

What condition is associated with TBCD p.His77Arg (c.230A>G)?

TBCD p.His77Arg (c.230A>G) is associated with TBCD-related disorder, early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome (ClinVar).

How common is TBCD p.His77Arg (c.230A>G) in the general population?

TBCD p.His77Arg (c.230A>G) is very rare (popmax 0.00447%, eas) (gnomAD).

What do computational predictors say about TBCD p.His77Arg (c.230A>G)?

AlphaMissense predicts likely benign (score 0.3093) — an in-silico prediction, not a clinical call.

TBCD p.His77Arg

c.230A>G · rs1409600874 · VCV624104

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.3093 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00447%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

TBCD-related disorder

Computational evidence

Protein change
AlphaMissense	0.3093	likely benign ⚠ discordant with ClinVar
REVEL	0.641	indeterminate
SaProt	LLR -13.11	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.24 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 2, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 190 kb · p 9.5e-05 · regional, not allelic
Overall
CADD	25.2	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 0.00447% East Asian · 2/44,780 alleles

Filtering AF 0.00074% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000277%

Overall 0.000186% 3/1,609,878 alleles · very rare exomes 3/1,457,562 · genomes 0/152,316 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00447%	22,390
South Asian	0.00111%	90,210

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.His77Arg
Coding: c.230A>G
MANE Select: NM_005993
dbSNP: rs1409600874
Type: single nucleotide variant
Location: chr17:82756210 (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

TBCD-related disorder

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

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.Arg113Ter 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-his77arg (accessed [today's date]).

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