Is TBCD p.Ala1159Val (c.3476C>T) pathogenic?

TBCD p.Ala1159Val (c.3476C>T) is classified Uncertain significance in TBCD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-04-25). AlphaMissense: likely benign (0.112); Ultra-rare (popmax 0.033%, mid); Associated with Inborn genetic diseases.

What condition is associated with TBCD p.Ala1159Val (c.3476C>T)?

TBCD p.Ala1159Val (c.3476C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TBCD p.Ala1159Val (c.3476C>T) in the general population?

TBCD p.Ala1159Val (c.3476C>T) is ultra-rare (popmax 0.033%, mid) (gnomAD).

What do computational predictors say about TBCD p.Ala1159Val (c.3476C>T)?

AlphaMissense predicts likely benign (score 0.112) — an in-silico prediction, not a clinical call.

TBCD p.Ala1159Val

c.3476C>T · rs375065191 · VCV1302398

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.112 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.112	likely benign
REVEL	0.079	moderately benign-leaning
SaProt	LLR -4.68	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 0.7	GERP 0.71, phastCons 0.16
Regional constraint	o/e 0.90	unconstrained · MANE · 190 kb · p 9.5e-05 · regional, not allelic
Overall
CADD	14.46	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 0.033% Middle Eastern · 2/6,058 alleles

Filtering AF 0.00582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.00124% 20/1,612,280 alleles · ultra-rare exomes 13/1,459,952 · genomes 7/152,328 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,029
East Asian	0.00892%	11,216
African / African-American	0.008%	12,507
South Asian	0.0011%	90,694
European (non-Finnish)	0.000594%	168,456

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.Ala1159Val
Coding: c.3476C>T
MANE Select: NM_005993
dbSNP: rs375065191
Type: single nucleotide variant
Location: chr17:82939473 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TBCD p.Ala1159= Likely benign ★ same residue
TBCD p.Gln330Ter Pathogenic ★★ same condition
TBCD p.Ala1162Val Uncertain significance ★★ ⚠ same condition
TBCD p.Ala394Ser Uncertain significance ★★ ⚠ same condition
TBCD p.Ala415Val Uncertain significance ★★ ⚠ same condition
TBCD p.Ala599Thr Uncertain significance ★★ ⚠ same condition
TBCD p.Ala907Val Uncertain significance ★★ ⚠ same condition
TBCD p.Arg1107Thr Uncertain significance ★★ ⚠ 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-ala1159val (accessed [today's date]).

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