Is TBCD p.Pro76Leu (c.227C>T) pathogenic?

TBCD p.Pro76Leu (c.227C>T) is classified Uncertain significance in TBCD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-12-19). AlphaMissense: likely benign (0.155); Very rare (popmax 0.00195%, nfe).

How common is TBCD p.Pro76Leu (c.227C>T) in the general population?

TBCD p.Pro76Leu (c.227C>T) is very rare (popmax 0.00195%, nfe) (gnomAD).

What do computational predictors say about TBCD p.Pro76Leu (c.227C>T)?

AlphaMissense predicts likely benign (score 0.155) — an in-silico prediction, not a clinical call.

TBCD p.Pro76Leu

c.227C>T · rs778788163 · VCV2429433

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.155 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00195%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.155	likely benign
REVEL	0.412	indeterminate
SaProt	LLR -10.55	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	GERP 2, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 190 kb · p 9.5e-05 · regional, not allelic
Overall
CADD	27.8	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 0.00195% European (non-Finnish) · 23/1,178,020 alleles

Filtering AF 0.0013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00109%

Overall 0.00155% 25/1,609,908 alleles · very rare exomes 22/1,457,736 · genomes 3/152,172 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00195%	51,218
Remaining individualsnot grpmax-eligible	0.0016%	62,318
South Asian	0.00111%	90,232

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.Pro76Leu
Coding: c.227C>T
MANE Select: NM_005993
dbSNP: rs778788163
Type: single nucleotide variant
Location: chr17:82756207 (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

Similar variants

TBCD p.Pro76= Likely benign ★ same residue
TBCD c.1224-2A>G Pathogenic/Likely pathogenic ★★ same type
TBCD c.2007-2A>G Likely pathogenic ★★ same type
TBCD p.Ala475Thr Pathogenic/Likely pathogenic ★★ same type
TBCD p.Ala554Val Pathogenic/Likely pathogenic ★★ same type
TBCD p.Arg113Ter Pathogenic/Likely pathogenic ★★ same type
TBCD p.Arg303Ter Pathogenic/Likely pathogenic ★★ same type
TBCD p.Arg323Ter Pathogenic/Likely pathogenic ★★ same type

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-pro76leu (accessed [today's date]).

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