Is TBCD p.Pro218Arg (c.653C>G) pathogenic?

TBCD p.Pro218Arg (c.653C>G) is classified Uncertain significance in TBCD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-17). AlphaMissense: likely benign (0.2151); Ultra-rare (popmax 0.025%, amr); Associated with Inborn genetic diseases.

What condition is associated with TBCD p.Pro218Arg (c.653C>G)?

TBCD p.Pro218Arg (c.653C>G) is associated with Inborn genetic diseases (ClinVar).

How common is TBCD p.Pro218Arg (c.653C>G) in the general population?

TBCD p.Pro218Arg (c.653C>G) is ultra-rare (popmax 0.025%, amr) (gnomAD).

What do computational predictors say about TBCD p.Pro218Arg (c.653C>G)?

AlphaMissense predicts likely benign (score 0.2151) — an in-silico prediction, not a clinical call.

TBCD p.Pro218Arg

c.653C>G · rs779456572 · VCV1476746

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2151 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.025%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2151	likely benign
REVEL	0.351	indeterminate
SaProt	LLR -9.99	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.9	GERP 2.4, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 190 kb · p 9.5e-05 · regional, not allelic
Overall
CADD	21.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.025% Admixed American · 15/59,998 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0124%

Overall 0.00093% 15/1,613,592 alleles · ultra-rare exomes 13/1,461,570 · genomes 2/152,022 · joint denominator

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.Pro218Arg
Coding: c.653C>G
MANE Select: NM_005993
dbSNP: rs779456572
Type: single nucleotide variant
Location: chr17:82781603 (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.Phe218Leu Uncertain significance ★ ⚠ 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-pro218arg (accessed [today's date]).

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