Is TBCE p.Ser195= (c.585C>T) pathogenic?

TBCE p.Ser195= (c.585C>T) is classified Conflicting classifications of pathogenicity in TBCE (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-15). Rare (popmax 0.315%, afr); Associated with hypoparathyroidism-retardation-dysmorphism syndrome.

What condition is associated with TBCE p.Ser195= (c.585C>T)?

TBCE p.Ser195= (c.585C>T) is associated with hypoparathyroidism-retardation-dysmorphism syndrome (ClinVar).

How common is TBCE p.Ser195= (c.585C>T) in the general population?

TBCE p.Ser195= (c.585C>T) is rare (popmax 0.315%, afr) (gnomAD).

TBCE p.Ser195=

c.585C>T · rs139440109 · VCV497269

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.315%, afr)

Conditions

hypoparathyroidism-retardation-dysmorphism syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.78 · evaluated, not missing
Pangolin	Δ0.21	loss · gain 0.06 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP -3.8	GERP -3.7
Overall
CADD	4.191	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.315% African / African-American · 236/74,994 alleles

Filtering AF 0.282% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.269%

Overall 0.0472% 761/1,613,268 alleles · rare exomes 592/1,461,078 · genomes 169/152,190 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.315%	318
European (non-Finnish)	0.0404%	2,473
Remaining individualsnot grpmax-eligible	0.0368%	2,715
East Asian	0.0201%	4,976
Admixed American	0.0117%	8,567
Finnishnot grpmax-eligible	0.00938%	10,664
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,570
South Asian	0.0022%	45,485

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.Ser195=
Coding: c.585C>T
MANE Select: NM_003193
dbSNP: rs139440109
Type: single nucleotide variant
Location: chr1:235430729 (GRCh38)
Gene constraint: LOEUF 0.868 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 89.27 · 6 PDB

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-ser195 (accessed [today's date]).

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