Is TBCE p.Pro453Ser (c.1357C>T) pathogenic?

TBCE p.Pro453Ser (c.1357C>T) is classified Uncertain significance in TBCE (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-25). AlphaMissense: likely benign (0.1112); Very rare (popmax 0.00333%, amr); Associated with Inborn genetic diseases.

What condition is associated with TBCE p.Pro453Ser (c.1357C>T)?

TBCE p.Pro453Ser (c.1357C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TBCE p.Pro453Ser (c.1357C>T) in the general population?

TBCE p.Pro453Ser (c.1357C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about TBCE p.Pro453Ser (c.1357C>T)?

AlphaMissense predicts likely benign (score 0.1112) — an in-silico prediction, not a clinical call.

TBCE p.Pro453Ser

c.1357C>T · VCV4181081

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1112 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.1112	likely benign
REVEL	0.074	moderately benign-leaning
SaProt	LLR -7.17	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 3.3	GERP 0.79, phastCons 0.96
Regional constraint	o/e 1.00	unconstrained · MANE · 69 kb · p 0.95 · regional, not allelic
Overall
CADD	19.69	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 0.00333% Admixed American · 2/59,978 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.00031% 5/1,613,762 alleles · very rare exomes 5/1,461,766 · genomes 0/151,996 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	29,989
Remaining individualsnot grpmax-eligible	0.0016%	62,504
African / African-American	0.00134%	74,900
European (non-Finnish)	8.48e-05%	1,179,926

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: TBCE
Protein: p.Pro453Ser
Coding: c.1357C>T
MANE Select: NM_003193
Type: single nucleotide variant
Location: chr1:235442869 (GRCh38)

Full TBCE 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

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/tbce-p-pro453ser (accessed [today's date]).

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