Is TBCD p.Ala127Pro (c.379G>C) pathogenic?

TBCD p.Ala127Pro (c.379G>C) is classified Uncertain significance in TBCD (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-08). AlphaMissense: ambiguous (0.3787); Ultra-rare (popmax 0.0107%, afr); Associated with Inborn genetic diseases.

What condition is associated with TBCD p.Ala127Pro (c.379G>C)?

TBCD p.Ala127Pro (c.379G>C) is associated with Inborn genetic diseases (ClinVar).

How common is TBCD p.Ala127Pro (c.379G>C) in the general population?

TBCD p.Ala127Pro (c.379G>C) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

What do computational predictors say about TBCD p.Ala127Pro (c.379G>C)?

AlphaMissense predicts ambiguous (score 0.3787) — an in-silico prediction, not a clinical call.

TBCD p.Ala127Pro

c.379G>C · VCV3324769

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3787 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3787	ambiguous
REVEL	0.14	moderately benign-leaning
SaProt	LLR -9.70	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.5	GERP -0.08, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 190 kb · p 9.5e-05 · regional, not allelic
Overall
CADD	20.1	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 0.0107% African / African-American · 8/74,866 alleles

Filtering AF 0.00528% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.00062% 10/1,613,254 alleles · ultra-rare exomes 7/1,461,154 · genomes 3/152,100 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0107%	9,358
Admixed American	0.00167%	59,914
South Asian	0.0011%	90,886

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.Ala127Pro
Coding: c.379G>C
MANE Select: NM_005993
Type: single nucleotide variant
Location: chr17:82766312 (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.Ala127Thr Uncertain significance ★ ⚠ same residue
TBCD p.Ala127= 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

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-ala127pro (accessed [today's date]).

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