Is TBCD p.Ala583Val (c.1748C>T) pathogenic?

TBCD p.Ala583Val (c.1748C>T) is classified Uncertain significance in TBCD (ClinVar, Single submitter, 1 submitter; last evaluated 2020-11-06). AlphaMissense: ambiguous (0.3889); Very rare (popmax 0.00225%, eas).

How common is TBCD p.Ala583Val (c.1748C>T) in the general population?

TBCD p.Ala583Val (c.1748C>T) is very rare (popmax 0.00225%, eas) (gnomAD).

What do computational predictors say about TBCD p.Ala583Val (c.1748C>T)?

AlphaMissense predicts ambiguous (score 0.3889) — an in-silico prediction, not a clinical call.

TBCD p.Ala583Val

c.1748C>T · VCV4937778

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3889 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00225%, eas)

Computational evidence

Protein change
AlphaMissense	0.3889	ambiguous
REVEL	0.481	indeterminate
SaProt	LLR -11.43	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 2.3, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 190 kb · p 9.5e-05 · regional, not allelic
Overall
CADD	24.3	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 0.00225% East Asian · 1/44,454 alleles

Overall 6.24e-05% 1/1,603,816 alleles · very rare exomes 1/1,451,450 · genomes 0/152,366 · 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.Ala583Val
Coding: c.1748C>T
MANE Select: NM_005993
Type: single nucleotide variant
Location: chr17:82903422 (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

Similar variants

TBCD c.1224-2A>G Pathogenic/Likely pathogenic ★★ same type
TBCD c.2007-2A>G Likely pathogenic ★★ same type
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TBCD p.Ala554Val Pathogenic/Likely pathogenic ★★ same type
TBCD p.Arg113Ter Pathogenic/Likely pathogenic ★★ same type
TBCD p.Arg303Ter Pathogenic/Likely pathogenic ★★ same type
TBCD p.Arg323Ter Pathogenic/Likely pathogenic ★★ same type
TBCD p.Arg436Ter Pathogenic ★★ same type

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-ala583val (accessed [today's date]).

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