Is TBCD p.Ala422Val (c.1265C>T) pathogenic?

TBCD p.Ala422Val (c.1265C>T) is classified Conflicting classifications of pathogenicity in TBCD (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-01-25). AlphaMissense: ambiguous (0.5034); Ultra-rare (popmax 0.024%, afr); Associated with Inborn genetic diseases.

What condition is associated with TBCD p.Ala422Val (c.1265C>T)?

TBCD p.Ala422Val (c.1265C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TBCD p.Ala422Val (c.1265C>T) in the general population?

TBCD p.Ala422Val (c.1265C>T) is ultra-rare (popmax 0.024%, afr) (gnomAD).

What do computational predictors say about TBCD p.Ala422Val (c.1265C>T)?

AlphaMissense predicts ambiguous (score 0.5034) — an in-silico prediction, not a clinical call.

TBCD p.Ala422Val

c.1265C>T · rs139015738 · VCV2386515

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5034 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.024%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5034	ambiguous
REVEL	0.304	indeterminate
SaProt	LLR -11.77	damaging
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.30 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.5	GERP 1.5, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 190 kb · p 9.5e-05 · regional, not allelic
Overall
CADD	30.0	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 0.024% African / African-American · 18/75,014 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0128%

Overall 0.0057% 92/1,613,530 alleles · ultra-rare exomes 74/1,461,290 · genomes 18/152,240 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.024%	4,167
South Asian	0.00989%	10,113
Remaining individualsnot grpmax-eligible	0.0064%	15,617
European (non-Finnish)	0.00492%	20,340
East Asian	0.00446%	22,418
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,598

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.Ala422Val
Coding: c.1265C>T
MANE Select: NM_005993
dbSNP: rs139015738
Type: single nucleotide variant
Location: chr17:82814881 (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.Ala422= Likely benign ★ same residue
TBCD p.Gln330Ter Pathogenic ★★ same condition
TBCD p.Ala1159Val Uncertain significance ★★ ⚠ 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

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-ala422val (accessed [today's date]).

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