Is TBCE p.Pro375= (c.1125C>T) pathogenic?

TBCE p.Pro375= (c.1125C>T) is classified Conflicting classifications of pathogenicity in TBCE (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-06-16). Ultra-rare (popmax 0.0178%, eas); Associated with hypoparathyroidism-retardation-dysmorphism syndrome.

What condition is associated with TBCE p.Pro375= (c.1125C>T)?

TBCE p.Pro375= (c.1125C>T) is associated with hypoparathyroidism-retardation-dysmorphism syndrome (ClinVar).

How common is TBCE p.Pro375= (c.1125C>T) in the general population?

TBCE p.Pro375= (c.1125C>T) is ultra-rare (popmax 0.0178%, eas) (gnomAD).

TBCE p.Pro375=

c.1125C>T · rs762683460 · VCV296306

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0178%, eas)

Conditions

hypoparathyroidism-retardation-dysmorphism syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4	GERP -3.6
Overall
CADD	0.771	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0178% East Asian · 8/44,882 alleles

Filtering AF 0.00883% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00641%

Overall 0.00198% 32/1,613,918 alleles · ultra-rare exomes 30/1,461,884 · genomes 2/152,034 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0178%	5,610
European (non-Finnish)	0.00186%	53,637
Remaining individualsnot grpmax-eligible	0.0016%	62,486
Finnishnot grpmax-eligible	0.00156%	64,020

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.Pro375=
Coding: c.1125C>T
MANE Select: NM_003193
dbSNP: rs762683460
Type: single nucleotide variant
Location: chr1:235438777 (GRCh38)
Gene constraint: LOEUF 0.868 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 89.27 · 6 PDB
Residue 375: the lrrct domain

Full TBCE gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hypoparathyroidism-retardation-dysmorphism syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TBCE c.100+1G>A Pathogenic/Likely pathogenic ★★ same condition
TBCE p.Arg12Ter Likely pathogenic ★★ same condition
TBCE p.Lys145Ter Pathogenic/Likely pathogenic ★★ same condition
TBCE c.898+6T>C Uncertain significance ★★ same condition
TBCE p.Ala149Gly Uncertain significance ★★ ⚠ same condition
TBCE p.Arg24His Uncertain significance ★★ ⚠ same condition
TBCE p.Cys141Tyr Uncertain significance ★★ ⚠ same condition
TBCE p.Cys371Tyr 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/tbce-p-pro375 (accessed [today's date]).

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