Is TBCD p.Ala626Ser (c.1876G>T) pathogenic?

TBCD p.Ala626Ser (c.1876G>T) is classified Uncertain significance in TBCD (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-10-22). AlphaMissense: likely benign (0.1232); Ultra-rare (popmax 0.0495%, mid).

How common is TBCD p.Ala626Ser (c.1876G>T) in the general population?

TBCD p.Ala626Ser (c.1876G>T) is ultra-rare (popmax 0.0495%, mid) (gnomAD).

What do computational predictors say about TBCD p.Ala626Ser (c.1876G>T)?

AlphaMissense predicts likely benign (score 0.1232) — an in-silico prediction, not a clinical call.

TBCD p.Ala626Ser

c.1876G>T · rs749225304 · VCV1334836

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1232 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0495%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1232	likely benign
REVEL	0.354	indeterminate
SaProt	LLR -7.80	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 2.3, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 190 kb · p 9.5e-05 · regional, not allelic
Overall
CADD	22.8	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 0.0495% Middle Eastern · 3/6,058 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00718%

Overall 0.00291% 47/1,612,652 alleles · ultra-rare exomes 43/1,460,284 · genomes 4/152,368 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0495%	2,019
Admixed American	0.0117%	8,552
South Asian	0.00331%	30,195
Remaining individualsnot grpmax-eligible	0.0032%	31,217
European (non-Finnish)	0.00271%	36,856

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.Ala626Ser
Coding: c.1876G>T
MANE Select: NM_005993
dbSNP: rs749225304
Type: single nucleotide variant
Location: chr17:82906007 (GRCh38)
Gene constraint: LOEUF 0.763 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.45 · 6 PDB
Residue 626: a UniProt-annotated variant site (in pebat; decreased protein abundance; does not affect localization to centrosome)

Full TBCD gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TBCD p.Ala626Thr Uncertain significance ★★ same residue
TBCD p.Ala626Val Uncertain significance ★ ⚠ same residue
TBCD c.1224-2A>G Pathogenic/Likely pathogenic ★★ same type
TBCD c.2007-2A>G Likely pathogenic ★★ same type
TBCD p.Ala475Thr Pathogenic/Likely pathogenic ★★ same type
TBCD p.Ala554Val Pathogenic/Likely pathogenic ★★ same type
TBCD p.Arg113Ter Pathogenic/Likely pathogenic ★★ same type
TBCD p.Arg303Ter Pathogenic/Likely 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-ala626ser (accessed [today's date]).

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