Is TBCD p.Ala415Val (c.1244C>T) pathogenic?

TBCD p.Ala415Val (c.1244C>T) is classified Uncertain significance in TBCD (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-12-18). AlphaMissense: likely benign (0.2335); Very rare (popmax 0.00659%, sas); Associated with Inborn genetic diseases.

What condition is associated with TBCD p.Ala415Val (c.1244C>T)?

TBCD p.Ala415Val (c.1244C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TBCD p.Ala415Val (c.1244C>T) in the general population?

TBCD p.Ala415Val (c.1244C>T) is very rare (popmax 0.00659%, sas) (gnomAD).

What do computational predictors say about TBCD p.Ala415Val (c.1244C>T)?

AlphaMissense predicts likely benign (score 0.2335) — an in-silico prediction, not a clinical call.

TBCD p.Ala415Val

c.1244C>T · rs763143236 · VCV429334

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2335 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00659%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2335	likely benign
REVEL	0.334	indeterminate
SaProt	LLR -10.02	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.42 · 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	25.0	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 0.00659% South Asian · 6/91,068 alleles

Filtering AF 0.00286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00195%

Overall 0.00211% 34/1,613,662 alleles · very rare exomes 33/1,461,528 · genomes 1/152,134 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0188%	5,330
South Asiangrpmax	0.00659%	15,178
East Asian	0.00446%	22,440
Remaining individualsnot grpmax-eligible	0.0032%	31,224
European (non-Finnish)	0.00102%	98,322

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala415Val
Coding: c.1244C>T
MANE Select: NM_005993
dbSNP: rs763143236
Type: single nucleotide variant
Location: chr17:82814860 (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

ZNF750 p.Pro415= 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.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-ala415val (accessed [today's date]).

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