Is TBCD p.Ala181Pro (c.541G>C) pathogenic?

TBCD p.Ala181Pro (c.541G>C) is classified Conflicting classifications of pathogenicity in TBCD (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-20). AlphaMissense: likely benign (0.0645); Rare (popmax 0.115%, mid); Associated with Inborn genetic diseases.

What condition is associated with TBCD p.Ala181Pro (c.541G>C)?

TBCD p.Ala181Pro (c.541G>C) is associated with Inborn genetic diseases (ClinVar).

How common is TBCD p.Ala181Pro (c.541G>C) in the general population?

TBCD p.Ala181Pro (c.541G>C) is rare (popmax 0.115%, mid) (gnomAD).

What do computational predictors say about TBCD p.Ala181Pro (c.541G>C)?

AlphaMissense predicts likely benign (score 0.0645) — an in-silico prediction, not a clinical call.

TBCD p.Ala181Pro

c.541G>C · rs201980005 · VCV1512664

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0645 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.115%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0645	likely benign
REVEL	0.077	moderately benign-leaning
SaProt	LLR -4.55	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 -0.27	GERP -4.6
Regional constraint	o/e 0.90	unconstrained · MANE · 190 kb · p 9.5e-05 · regional, not allelic
Overall
CADD	0.777	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 0.115% Middle Eastern · 7/6,084 alleles

Filtering AF 0.054% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0383%

Overall 0.0164% 265/1,613,902 alleles · rare exomes 235/1,461,692 · genomes 30/152,210 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.115%	869
Remaining individualsnot grpmax-eligible	0.0304%	3,288
South Asian	0.0274%	3,644
Admixed American	0.0183%	5,455
European (non-Finnish)	0.0167%	5,989
African / African-American	0.00534%	18,732
Finnishnot grpmax-eligible	0.00312%	32,006

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.Ala181Pro
Coding: c.541G>C
MANE Select: NM_005993
dbSNP: rs201980005
Type: single nucleotide variant
Location: chr17:82768525 (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.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
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-ala181pro (accessed [today's date]).

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